MORFOLOGIE NORMAL I PATOLOGIC

ORGANUL GIRALDES RUDIMENT SAU STRUCTUR FUNCIONAL N

COMPONENA COMPLEXULUI FUNICULOTESTICULAR
Mihail tefane, Angela Babuci, Tamara Titova, Zinaida Zorina, Olga Belic
Catedra Anatomia Omului USMF Nicolae Testemianu
Summary
The Giraldes' organ a rudiment
or a functional structure of the funiculotesticular complex in man
The Giraldes' organ represents a stable formation, consisting of convoluted system of
canalicles that possesses a well developed glomerular vascular system, which forms anastomoses
with the vessels of other components of the funiculotesticular complex. It was not found in
laboratory animals and can be considered as a new phylogenetic organ, whose functional
peculiarities are not known yet.
Rezumat
Organul Giraldes reprezint o formaiune stabil, constituit dintr-un sistem de canalicule
contorte i vezicule ce posed un sistem vascular glomerular bine dezvoltat, care formeaz
anastomoze cu vasele celorlalte componente ale complexului funiculotesticular (CFT). El nu se
depisteaz la animalele de laborator i poate fi considerat ca organ filogenetic nou,
particularitile funcionale ale cruia sunt nc neclare.
Actualitatea
Complexul funiculotesticular reprezint o formaiune destul de complicat. Cercetarea
componentelor acestui complex ct i a corelaiilor dintre ele, la fel, i a mecanismelor
interaciunii lor prezint una din direciile principale de dezvoltare a andrologiei teoretice
moderne, pe care se poate baza practica tratamentului sterilitii masculine. n literatura de
specialitate pot fi ntlnite doar informaii fragmentare despre morfologia unor elemente aparte
ale cordonului spermatic fr careva referiri la relaiile lor reciproce. La etapa actual a
dezvoltrii andrologiei ca tiin, aceste aspecte capt o importan primordial. Fr o studiere
a topografiei i a particularitilor morfologice ale organului Giraldes i a corelaiilor sale cu
vasele sangvine i limfatice, cu elementele musculare este dificil de a obine o imagine complet
despre structura i specificul activitii organelor reproductive masculine. Datele anatomice de
care dispunem n prezent, nu satisfac pe deplin nici cerinele andrologiei i nici pe cele ale
microchirurgiei contemporane.
Avansarea andrologiei chirurgicale, a microchirurgiei, transplantologiei, actualizarea
problemelor de transformare a sexului necesit o studiere macromicroscopic complex i
detaliat a cordonului spermatic i a testiculului.
Obiective
Scopul actualului studiu vizeaz evaluarea unor particulariti de vrst, topografice i ale
vascularizaiei i ncercarea de a pune n eviden importana lui n activitatea normal a
testiculului.
Material i metode
Studiul complex a elementelor organului Giralde, a trsturilor morfologice, formei i
topografice este realizat pe piesele anatomice integrale colorate cu reactivul Schiff.
23

Microstructura a fost cercetat prin tratarea pieselor histologice cu hematoxilin-eozin dup

Van-Geison. Investigaiile sau efectuat pe 80 piese ale CFT.
Rezultate i discuii
Despre organul Giraldes se amintete numai n cteva lucrri (3, 5), care consider c,
paradidimusul, sau organul Giraldes prezint o formaiune rudimentar, ce se dezvolt din
canaliculele pronefrosului i corespunde paraoforonului la femeie. De unii autori el este apreciat
ca rmi a canaliculelor paramezonefrotice (1). Conform datelor (2, 4) acest organ se
deosebete de hidatide prin faptul c el nu se fixeaz nemijlocit de tunica albugenee a testiculului
i a epididimusului. Autorii menionai prezint hidatidele ca rudimente ale canalului Muller. Noi
presupunem c aceste formaiuni se difereniaz din celulele germinale primordiale care la
nceput apar n sptmna a 6-a n pereii veziculei viteline i ulterior migreaz la nivelul
gonadei.
Rezultatele investigaiilor noastre ne demonstreaz c la adult acest organ reprezint un
sistem complicat de canalicule i vezicule cu o mare diversitate de form i dimensiuni, care se
depisteaz permanent de ambele pri i este localizat mai frecvent la nivelul capului i coadei
epididimusului i printre elementele poriunii scrotale ale cordonului spermatic.

Fig. 1. Organul Giraldes la ftul de 7 luni. 1 lobuli ai organului.

Coolorat cu reactivul Schiff x 8.
Dimensiunile i formele organului sunt destul de variate. n dezvoltarea lui pot fi
evideniate dou perioade prima, pn la vrsta de 3 4 ani i a doua (de accelerare) la vrsta
de 11 14 ani. La ft i nou-nscut organul Giraldes este constituit dintr-un sistem de canalicule
contorte slab pronunate, sau de nite fragmente, insulie, izolate una de alta (fig. 1), sau de
canalicule contorte, ce se termin cu dilatri de diferit form i dimensiuni, slab vascularizate i
avasculare. La adult, spre deosebire de ft i copil aceste structuri sunt nzestrate cu bogate reele
de vase sangvine, ce constituie nite formaiuni vasculare glomerulare (fig. 2).
La acest organ deosebim hil prin care n el ptrund vase sangvine, nervi i iese venele. n
componena sistemului vascular evident predomin venele, ce ne informeaz indirect despre
prezena unui metabolism nalt n aceste formaiuni.
Din punct de vedere macromicroscopic aceste structuri nu pot fi considerate ca paradi
dim, deoarece ele sunt situate departe de testicul i epididim, printre elementele funiculului
spermatic. Noi le-am depistat n poriunea scrotal superioar printre ansele plexului
pampiniform i n straturile superficiale ale cordonului spermatic (fig. 3).

24

Fig. 2. Organul Giraldes in poriunea scrotal, nzestrat cu o bogat reea

vascular. Coolorat cu reactivul Schiff x 6.

Fig. 3. Organul Giraldes in starturile superficiale ale plexului pampiniform;

poriunea scrotal. Colorat cu reactivul Schiff x 8.

Fig. 4. Oranul Giraldes; la un subiect de 18 ani. 1 veziculele organului;

2 canaliculele intervezicale; 3 vase sangvine. Coolorat cu reactivul Schiff x 8.
25

Fig. 5. Organul Giraldes in poriunea scrotal a funiculului spermatic.

Colorat cu reactivul Schiff x 10.
Se determin nu numai organe solitare, dar i conglomerri de la 2 pn la 5 6 (fig. 4)
unde fiecare din ele posed hil aparte i un sistem vascular glomerular individual. Froma acestor
elemente este destul de variat. Ele n-au nici o legtur cu testiculul sau epididimusul, sunt
nconjurate de o capsul fin de esut adipos i posed o bogat reea vascular. Printre lobului
capsului adipoase a cordonului spermatic se evideniaz lobuli separai ai acestui organ ale cror
reele vasculare glomerulare anastomozeaz ntre ele (fig. 5).
Organul Giraldes este vascularizat de ramurile arterei testiculare sau diferenial.
Predomin tipul divergent de vascularizare, ns se ntlnete i cel magistral. n componena
reelei vasculare pot fi determinate cteva straturi: intern, alctuit din anse capilare fine ce ader
intim la pereii canaliculelor; mediu format din arteriole i venule bine pronunate la nivel
mezoscopic i extern, constituit din vase mai bine dezvoltate, ce formeaz un plex vascular cu
anse mari. Aceste vase au un caracter sinuos bine pronunat. Refluxul sngelui venos are loc prin
intermediu a unei sau a dou vene, care trec prin hil mpreun cu vasele limfatice i ntr n
componena pediculului vascular. Venele au un perete subire i se deosebesc de cele ale plexului
pampiniform.
Pe piesele histologice se observ c din interior acest organ este acoperit cu epiteliu cubic
sau ciliat prismatic. Organul Giraldes nu se depisteaz la cnii, pisici i obolani.
Deci organul Giraldes din CFT reprezint o formaiune stabil, alctuit dintr-un sistem
nchis de canalicule contorte i vezicule ce posed un sistem vascular glomerular. n baza
rezultatelor obinute, lund n consideraie sistemul lui vascular bine dezvoltat i prezena
multiplelor anastomoze cu vasele celorlalte componente ale CFT, organul Giraldes poate fi
considerat ca un component activ, cu rol important n distribuirea sngelui, la fel i la meninerea
unei temperaturi constante a sngelui n artera testicular.
El nu se evideniaz la animalele de laborator i deaceea poate fi apreciat ca un organ
filogenetic nou, particularitile funcionale ale cruia sunt nc neclare.
Bibliografie
1. Andronescu A. Anatomia dezvoltrii omului. Embriologie medical. Bucureti, 1987,
Edit. medical, 246 p.
2. Keily E. A. Scentific basis of testicular, descent and management implications for
cryptorchidism. Britisch Journal of Clinical Practice. 48(1): 37 41, 1994.
3. Tillaux P. Topographie anatomie, 1896.
4. Trosic A. Ucestalost makromorfoloske Karakteristike apendiksa testis. Lijecn. vjesn.,
1980, 102, 7 8, 395 399.
5. . . . 3, , 1910.
26

VARIABILITATEA RAPORTURILOR NEUROVASCULARE LA NIVELUL ARCULUI

AORTIC
Tamara Hacina
Catedra Anatomia Omului
Summary
Variabilities of neurovascular relationships at the level of the aortic arch
The author describes a subject of special interest in the surgery of the mediastinum : the
positions and relations of the left vagus and left recurrent laryngeal nerve, with special reference
in the superior mediastinum , at the level of the arch of aorta. A study was undertaken to identify
peculiarities of topography of these nerves related to the type of the human body constitution
with applied clinical significance. Variability of both nerves traject, of insertion of the arterial
ligament
to aorta, as the
existence of
supernumerary trunk of
the
left recurrent nerve and thoracic duct lymph were detected.
Rezumat
Autorul abordeaz un
subiect ce are
o
anumit
importan
n chirurgia mediastinului: localizrile i corelaiile nervului vag i ale celui laringean recurent
stngi, cu referire la mediastinului superior, la nivelul arcului aortic. Acest studio a
fost realizat pentru identifica particularitile anatomotopografice individuale i de tip
constituional ale corpului uman, ce au un rol clinic aplicat. A fost depistat att variabilitatea
traiectului nervilor, a inseriei ligamentului aortal, ct i existena a trunchiurilor supranumerare
ale nervului recurent stng i a ductului limfatic toracic.
Actualitatea
Tendina creterii cazurilor de pareze i a paralizii ale plicilor vocale n ultimii ani se poate
explica prin frecvena sporit a interveniilor chirurgicale pe organele toracice, ce au legturi
sintopice cu nervul recurent, n special, pe cro aortic. La efectuarea mediastinoscopiei, a
analgeziei interpleurale, a lobectomiei plmnului stng, n limfadenectomie, mai ales n plastia
arcului aortic, o atenie deosebit necesit evidenierea variabilitii traiectului nervului vag i al
nervului recurent stngi pentru profilaxia complicaiilor postoperatorii. Chirurgia toracic, n
special cea cardiovascular, sunt asociate cu diferite complicaii, inclusiv paralizia coardelor
vocale, cauzat de lezarea intraoperatorie a nervului recurent. Traumele intraoperatorii a nervului
recurent stng au loc n 11-32% de intervenii chirurgicale. E de remarcat, c literatura la aceasta
tem conine puine informaii despre datele antropometrice, ce influeneaz sintopia organelor
mediastinului superior, dei prognozarea preoperatorie a localizaiei nervului vag i al celui
recurent laringean stng vor contribui la reducerea riscului de deteriorare a lor intraoperatorie.
Scopul
Diminuarea riscului traumatizrii intraoperatorii a nervului vag i al celui recurent
laringean stng pe baza prognozrii particularitilor individuale ale acestora.
Obiectivele
1. Studierea variabilitii individuale i de constituie a raporturilor nervului vag i al celui
recurent stngi cu arcul aortei i ramurile ei.
2. Contribuia alegerii optime a reperelor pentru vizualizarea intraoperatorie a nervilor susnumii.
Materiale i metode
Materialul de studiu include 98 de complexe mediastinale umane ale persoanelor ce difer
ca sex i vrst i tip constituional, cel mult 24 de ore dup deces. Particularitile individuale
sintopice ale arcului aortic, ale nervilor adiaceni (nervul vag i cel recurent din stnga) i ale
27

ductului limfatic toracic au fost examinate prin prepararea anatomic i aplicarea metodelor
antropometrice. Toate preparatele au fost fotografiate cu camera digital.
Rezultatele i discuii
Conform noiunii, arcul aortic (ArA) este segmentul aortei localizat ntre originea
trunchiului brahiocefalic i artera subclavicular stng.
Numrul i ordinea pornirii ramurilor lui sunt foarte
variabile. Acest fapt se explic prin embriogeneza
complex. Arcul aortic poate fi brusc curbat sau uor
curbat. n cel dinti caz, toate ramurile lui pornesc de
la un sector mai scurt dect n situaia de curb
aplatisat. Dispersarea ramurilor n arcul plat curbat
trebuie se fie luat n eviden n timpul efecturii
aortografiei transcarotide. Lungimea medie a arcului
aortic este de 4,3 cm. La maturi, cel mai scurt arc
observat de noi era de 2,7 cm, iar cel mai lung - de
6.0 cm.
Studiile sintopiei organelor mediastinului superior pe
98 de preparate au demonstrat variabilitatea larg a
Fig.1. Arcul aortic brusc curbat.
corelaiilor interorganice i a traiectului nervilor i al
1 trunchiul brahiocefalic; 2
vaselor adiacente. Acest fapt are o importana
artera carotid comun stng; 3
practic deosebit. Atenie special a fost acordat
artera subclavicular stng; 4
momentelor eseniale pentru vizualizarea mai rapid
artera pulmonar dreapt; 5 traheea;
a nervilor n discuie pe parcursul interveniilor
6 ezofagul; 7 nervul vag stng; 8
chirurgicale. Pe de o parte, o asemenea abordare
ductul arterial; 9 devierea atipic
contribuie la profilaxia traumrii nervilor, iar de pe
a nervului recurent stng; 10 nodul
alt parte, dac aceasta a avut loc, la alegerea
limfatic; 11 - nervul recurent stng.
variantei
mai
potrivite
a
tehnicii
neuromicrochirurgicale, n cazul efectuarii reinervaiei. Problema traumrii nervilor vag i cel
laringean din stnga provoac discuii largi n rndul clinicienilor [4,6,8].
n linii generale, am obinut rezultate similare, ce se refer la organele adiacente arcului
aortic, altor autori:
- anterior, arcul aortei este acoperit de pleura, de marginile anterioare ale plmnilor i de
timus;
- n partea anteromedial a nervului vag este situat nervul frenic stng, n cea anterosuperioar a
arcului aortei - vena brahiocefalic stng;
- mai jos de arcul aortei se afl artera pulmonar stng i bronhul stng; intersectndu-le,
arcul aortic urmeaz n poriunea descendent;
- pe semicircumferina anteroinferioar a arcului aortei se insereaz ligamentul arterial - ductul
arterial (Botall) obliterat;
- n partea posterioar a arcului aortei se situeaz traheea, esofagul, ductul limfatic toracic;
- de la suprafaa superioar a arcului aortic n direcie cranian i iau nceputul trunchiul
brahiocefalic, artera carotid comun stng i artera subclavicular stng;
- din dreapta se localizeaz poriunea ncepient a venei cave superioare;
- din toate prile arcul aortic este nconjurat de ramurile trunchiurilor simpatice i ale nervilor
vagi, ce formeaz plexul cardiac.
Mai e de completat unele raporturi interorganice, ce au importan practic. Poriunea
mijlocie a arcului nu este acoperit de pleura, ceea ce e utilizat de medici la efectuarea anesteziei
retrosternale a plexului cardiac. ntre nervul frenic i nervul vag trece vena intercostal suprema
stng, avnd o direcie oblic anterosuperioar, iar sub arc se localizeaz 4-6 noduli limfatici cu
mrimea de 0,5-1.0 cm. n interiorul toracelui nervul recurent stng se afl n contact strns cu
aorta, cu traheea, cu atriul stng, cu bronhul principal stng, cu esofagul i cu noduli limfatici.
28

Fiind n contact strns cu diferite structuri anatomice, nervul vag i cel recurent laringean stngi
sunt extrem de vulnerabili att n condiiile lor patologice, cum ar fi aneurismele aortale,
dilatrile atriului stng n stenoza mitral sau aortic, tumorile mediastinale, ale bronhiilor
principali i ale plmnului stng, ct i n timpul interveniilor chirurgicale. Localizarea
nervului recurent stng n contact direct cu artera pulmonar necesit o atenie deosebit n
timpul ligaturrii i seciunii acestui vas. Disecia efectuat ntre trahee i aort cauzeaz tracia
nervului recurent stng, dereglrile frecvente ale nervului laringean n timpul mediastinoscopiei
se explic prin acest mecanism de leziune indirect. In cazul unor traumatisme intratoracice sau a
tumorilor, cel mai des sunt lezati nervii recureni, mai ales cel de pe partea stng.
Clinicienii evideniaz trei zone ce se refer la riscul de deteriorare
a nervului recurent stng:
a) zona de risc sczut de-a lungul peretelui drept i naintea poriunii superioare a peretelui
anterior al traheei;
b) zona de risc nalt a leziunilor indirecte induse de compresiuni - ntre partea inferioar a
peretelui traheei i aorta;
c) zona de risc ridicat de vtmare direct - naintea poriunii inferioare a peretelui stng al
traheei.
Rezultatele cercetrii noastre ne piermit completarea informaiei urmtoare din sursele
bibliografice: nervul vag stng intersecteaz arcul
aortei n partea anterioar, ramura lui - nervul
recurent laringean - l ocoleste inferior, lng
ligamentul arterial, apoi posterior i trece prin
anul traheoezofagian anterior. Astfel, traiectul
nervului vag stng pe faa anterioar a arcului
variaz de la cel pracic vertical la oblic, sub
unghiul ascuit fa de planul orizontal (Figg.2,4).
Distana ntre nervul recurent i ligamentul arterial
la fel variaz de la contact strns pn la 1.0 cm;
iar
localizarea
acestui
nerv
n
anul
traheoezofagian se atest numai n 58% de cazuri .
n descrierile clasice nervul vag stng trece
anterior de poriunea incipient a arterei
subclaviculare stngi i intersecteaz faa
Fig.2. Arcul aortic uor curbat cu
anterioar a poriunii stngi a arcului aortic.
cinci ramuri.
Dup rezultatele cercetrii noastre n 46% se atest
1 trunchiul brahiocefalic; 2 artera
alte raporturi: n 32% nervul trece lateral pn la
carotid comun dreapt; 3 arteria
2,5 cm; n alte cazuri mai medial (Figg.2,3,4).
tiroida ima; 4 artera carotid comun
n literatura de specialitate sunt multe descrieri ale
stng; 5 artera subclavicul stng; 6
traiectului anomalos ale nervului vag stng i a
nervul vag stng; 7 - nervul recurent
celui recurent [1,2,7].
stng; 8 ductul arterial.
N-a fost depistat proporionalitatea direct ntre
lungimea arcului i a tipului constituional, ntre
numrul de ramuri i lungimea arcului.
Nu exist legiti referitoare la corelaiile neurovasculare n situaii cu un numr divers de
ramuri ale arcului. Deci localizarea lateral a nervului vag a fost atestat la arcuri cu 3 i 5
ramuri, iar cea medial, n cazul de patru ramuri (Figg.1,2,4). Nici numrul de ramuri nu depinde
de forma i de lungimea arcului. Aadar, trei ramuri au fost constatate la arcurile aortice cu o
lungime de la 2,7 pn la 5,0 cm; patru ramuri la arcuri cu o lungime de la 4,2 pn la 6,0 cm.
Au fost constatate arcuri de 5 cm lungime doar cu dou ramuri i de 5,7 cm cu cinci (Figg.2,3).
Este evident, corelaiile nervilor adiaceni arcului nu pot fi similare n diferite cazuri.

29

n regiunea gtului riscul traumrii nervului vag stng este mai mare dect al celui drept,
din cauza particularitilor de corelare cu artera tiroid inferioar. n regiunea toracelui mai
frecvent are loc traumarea nervului laringean stng.
n 88 % de cazuri nervul recurent stng pornete de la suprafaa dorsomedial a nervului
vag, n 12% - de la cea medial, pe faa anterioar a arcului. n poriunea iniial, sub arcul
aortei, posterior de triungiul Gross, el
contacteaz strns cu 3-5 ganglioni limfatici
de dimensiuni mari (0.5-1.0 cm). La acest
nivel nervul recurent repet configuraia lor,
iar n caz de creterea lor n dimensiuni, se
aplatiseaz esenial, devenind de 2-3 mai
subire dect iniial. Acest fapt poate duce la
modificri fonetice, greu diagnosticabile din
partea laringelui.
n 10 % de cazuri, nervul recurent este
reprezentat de dou sau trei trunchiuri.
Conform datelor lui C.Weeks, J.Hinton
Fig.3. Arcul aortic uor curbat cu dou
(1942), acest fenomen este ntlnit n 78%
ramuri.
de cazuri; n conformite cu observaiile pe
1 originea comun a trunchiului
cini ce aparin lui Iakovleva I.A. (1966) n
brahiocefalic cu artera carotid comun stng;
25%.
2 trunchiul brahiocefalic; 3 artera carotid
Este evident distribuirea lor permanent n
comun stng; 4 artera subclavicular
plan frontal unul fa de altul. Distana
stng; 5 nervul vag stng; 6 traheea; 7 dintre trunchiuri pe faa posterioar a
nervul recurent stng; 8 ductul arterial; 9
poriunii concave a arcului aortal variaz de
originea tipic a nervului recurent; 10 nodul
la 2 mm pn la 5 mm, ns la nivelui feei
limfatic.
ei convexe 10-14 mm (fig.4 ).
Un interes practic prezint faptul c toate cazurile
de trunchiuri supranumerare au fost observate la
persoanele de tip constituional brahimorf. n
diferite surse de literatur didactic se descrie
divizarea nervului recurent laringean n dou
ramuri (medial i lateral) la nivelul limitei
inferioare a laringelui. Probabil, existena mai
multor trunchiuri ale nervului recurent se poate
explica prin divizarea lui inferioar.
Am observat o legitate: trunchiurile supranumerare
ale nervului recurent stng se depisteaz n cazuri
n care nervul vag stng intersecteaz marginea
convex a arcului aortic n aproximitatea originii lui
Fig.4. Arcul aortic plat curbat cu
(fig. 4). Aadar, pe baza vizualizrii intraoperatorii
patru ramuri.
a nervului vag se poate prognoza topografia
1 trunchiul brahiocefalic; 2 artera
individual a nervului recurent stng, ce la rndul
carotid comun stng; 3 artera
su permite diminuarea riscului de traumare a
vertebral stng; 4 artera
ultimului.
subclavicular stng; 5 traiectul
n studiul nostru au fost depistate variantele
atipic al nervului vag stng; 6
ramificrii arcului aortic i ale inseriei
traheea; 7 trunchiurile nervului
ligamentului arterial, traiectele atipice ale nervului
recurent stng; 8 ezofag; 9 ductul
vag stng i ale nervului recurent, existena
arterial.
trunchiurilor supranumerare ale ultimului, prezena
ductului toracic limfatic dublu.
30

Descrierea clasic a corelaiei arcului aortic cu structurile localizate posterior de el este

urmtoarea [9]. Faa posterioar a arcului aortic contacteaz cu peretele anterior al traheei. Spre
stnga, la nivelul de trecere a arcului n aorta descendent, se localizeaz ezofagul. n anul
traheoezofagial anterior trece nervul recurent, iar de-a lungul marginii stngi a ezofagului ductul limfatic toracic. Figurile 1 i 4 demonstreaz variabilitatea raporturilor interorganice a
aortei cu organele localizate posterior.
Potrivit observaiilor noastre, localizarea nervului recurent stng n anul traheoezofagial
anterior are loc numai n 61%. n 39%, el trece cu 3-10 mm mai medial de an, n faa
anterioar a ezofagului.
Distana ntre trunchiul brahiocefalic i artera carotid comun stng variaz de la 1 mm
pn la 6 mm, ntre artera carotid comun stng i artera subclavicular stng de la 2 mm
pn la 2 cm. Forma, dimensiunile arcului aortic, raporturile dintre ramurile lui nu depind de sex
i tip constituional. Trebuie de remarcat c la normostenici lungmea medie a aortei este de 4,17
cm (cu variabilitatea de la 3,0 cm pn la 6,0 cm), iar la brahimorfi 4,12 (cu diapazon de la 3,5
cm pn la 4,8 cm).
Concluzii
1. Sintopia organelor mediastinului superior este foarte variabil, sintopia tipic fiind numai n
50%.
2. Raporturi interorganice tipice se atest la nervul vag stng n 54%, la nervul recurent n
58%, la ductul toracic limfatic 85%, la ligamentul arterial n 50%.
3. Nu se observ dependena lungimii arcului aortic, raporturilor dintre ramurile lui, de tip
constituional i sex.
4. A fost constatat numai o legitate, cunoaterea creia poate contribui la diminuarea cazurilor
de traumatizare a nervului recurent: trunchiurile supranumerare ale nervului recurent stng
se atest numai la persoanele la care nervul vag stng intersecteaz limita poriunii convexe
a arcului aortic n jumtatea lui dreapt
Bibliografie
1. Doyle JL, Watkins HO, Halbert DS. Undescended laryngeal nerve Tex Med 1967;63:53-56.
2. Galetta D. Cesario A. Margaritora S. Granone P. Anomalous intrathoracic left vagus
and recurrent laryngeal nerve course. Annals of Thoracic Surgery, 2008, 86(2):654-5.
3. Henry JF, Audiffret J, Denizot A, Plan M. The nonrecurrent inferior laryngeal nerve: review
of 33 cases, including two on the left side Surgery 1988;104:977-984.
4. Levi A. C., Masenti E., Nano M.. A contribution to the topographical anatomy of the
recurrent laryngeal nerve (nervus laryngeus recurrens) and the mediastinal connective tissue.
Surg.and radiol. Anatomy, 1982, Vol. 4, N3, 205-209.
5. Premachandra D.J., Radcliffe G.J., Stearns M.P. Intraoperative identification of the recurrent
laryngeal nerve and demonstration of its function. Laryngoscope 1990; 100:94-96.
6. Rowe Jones J.M., Leighton Sej, Rosswick R.P.. Benign thyroid disease and vocal cord
palsy. Ann R Coll Surg Eng 1993; 75(4): 241-244.
7. Sanders George, Uyeda Robert Y., Karlan Mitchell S. Nonrecurrent inferior laryngeal nerves
and their association with a recurrent branch. The American Journal of Surgery, 1983,
Volume 146, Issue 4: 501503.
8. Titche L.L.. Causes of recurrent laryngeal nerve paralysis. Arch Otolaryngol 1976; 102 : 259261.
9. .. . ,1964.

31

DENSITATEA MACROFAGELOR N CADRUL PROGRESIEI NEOPLAZIEI DE

CERVIX UTERIN
Lilian aptefrai, Vitalie Mazuru, Lucian Rudico, Valeriu David, Veaceslav Fulga
Catedra Histologie, Citologie i Embriologie
Summary
Macrophagal density within the cervical neoplasia progression
In this study we present the density, distribution and morphological pecuilarities of CD68
positive macrophages within the progression of uterine cervix neoplasia. Based on obtained
results, we can conclude that CD68 positive macrophage density increases gradually as cervical
neoplasia progresses reaching the highest value in the squamous cell invasive carcinoma stage.
CD68 positive macrophages are ubiquitos in the neoplasic epithelium, where they present
different size and frequently may be multinucleated.
Rezumat
In acest studiu prezentm densitatea, distribuia i particularitile morfologice ale
macrofagelor CD68 pozitive n cadrul progresiei neoplaziei de cervix uterin. n baza rezultatelor
obinute, putem concluziona c densitatea macrofagelor CD68 pozitive sporete pe msura
progresiei neoplaziei de col uterin, atingnd valori maxime n cazurile cu carcinoame
scuamocelulare franc invazive. Macrofagele CD68 pozitive sunt omniprezente n epiteliul
neoplazic, unde au dimensiuni mai mari i pot fi multinucleate.
Introducere
Dvorak H.F. (1986) a definit tumora drept o plag care nu se vindec [2]. Infiltrarea
leucocitelor n esutul neoplazic poate fi privit drept un rspuns antitumoral, dar sunt numeroase
date tiinifice care confirm c macrofagele i limfocitele activate din acest infiltrat sunt surse
majore de citokine proinflamatoare, factori de cretere i factori angiogenici. Mai mult, exist
opinii conform crora inflamaia protejeaz tumorile de rspunsul imun [12]. Datele recente
sugereaz c macrofagele au un rol important n invazia tumoral, n proliferarea celular i
supravieuirea metastazelor apropiate i la distan [8].
n condiii normale, din monocitele sanguine extravazate n esutul conjunctiv se dezvolt
un tip specific de macrofage rezidente, care ndeplinesc un ir de funcii cum ar fi:
recunoaterea, captarea i digestia celulelor alterate, a ECM, microorganismelor i substanelor
exogene; implicarea n reaciile imune; remodelarea tisular; reglarea turnoverului celular
normal [17]. Pe de alt parte, macrofagele reprezint componentul major al infiltratului
inflamator n tumorile primare i secundare, unde au un fenotip distinctiv i sunt numite
macrofage asociate tumorii (TAM) [8]. TAM au un fenotip relativ imatur, caracterizat prin
expresia slab a antigenilor macrofagelor difereniate, carboxipeptidazei M, CD51, prin expresia
nalt a IL-1 i IL-16, expresia joas a factorului necrozei tumorale- (TNF-) [7]. Bineneles,
expresia acestor markeri variaz n limite largi n funcie de tumori i chiar diferite arii tumorale
[8]. Spre deosebire de macrofagele esutului normal, TAM din tumorile experimentale au
abiliti foarte reduse de a leza celulele tumorale, de a prezenta antigenele tumorale Tlimfocitelor i de a expresa citokinele imunostimulatorii pentru proliferarea i funcia
antitumoral ale limfocitelor T i NK [3]. Macrofagele au abilitatea de a-i modifica rapid
profilul funcional drept rspuns la modificrile din microanturajul lor, transformndu-se ntr-un
suport pentru celulele tumorale [12, 16]. Dup modelul clasificrii Th1/Th2, dou extreme ale
macrofagelor au primit nume de M1 i M2 macrofage [10]. Macrofagele M1 au aciune
antitumoral, exprim lipopolisaharidele i interferonul-. Macrofagele M2 susin progresia
tumoral, exprim IL-4, IL-13 i alte citokine proprii limfocitelor Th2 [15].
n progresia tumoral, TAM sunt implicate prin mai multe mecanisme. Astfel, TAM
situndu-se sub membrana bazal n zona de invazie tumoral, faciliteaz acest proces prin
mecanismul de inducie a ciclooxigenazei-2 [15]. TAM secret intens MMPs (metaloproteinaze
32

matriceale), n special MMP9 [5, 8,]. n mai multe tumori infiltraia cu TAM coreleaz pozitiv cu
proliferarea tumoral, estimat prin MIB-1, Ki67 sau indicele mitotic [8]. Acest lucru se explic
prin faptul c TAM elimin mai muli factori care stimuleaz proliferare i supravieuirea
celulelor tumorale. Printre aceti factori pot fi menionai EGF (epidermal growth factor), PDGF
(plateled-derived growth factor), VEGF (vascular endothelial growth factor), HGF (hepatocyte
growth factor) i bFGF (basic fibroblast growth factor) [9].
Majoritatea autorilor coreleaz numrul mare de macrofage n tumori cu un prognostic
nefavorabil [8]. n literatura de specialitate exist puine date despre rolul macrofagelor n
neoplazia de col uterin. Conform Kobayashi A. i col (2008), densitatea macrofagelor CD68
pozitive crete pe msura sporirii severitii neoplaziei, iar expresia MMP-9 de ctre aceste
celule este maximal n CIN3 (neoplazie cervical intraepitelial) [5]. Davidson B. i col (1999)
susin c densitatea macrofagelor nu coreleaz cu supravieuirea n cancerul cervical [1], iar
Gonalves M.A. i Donadi E.A. (2004) afirm c prezena macrofagelor ar putea fi un indicator
al regresiei leziunii [4].
Material i metode
Specimenele i procesarea primar. n studiul prezent au fost prelevate i incluse biopsiile
intite din leziuni evidente macroscopic, materialul postoperator i piesele de conizaie.
Materialul colectat a fort prelucrat dup tehnica histologic uzual, fixat n formalin i
incluzionat n parafin.
Histopatologie. Din fiecare bloc au fost efectuate seciuni n serii cu grosimea de 3 m
grosime. Seciunile iniiale au fost colorate cu metoda hematoxilin-eozin pentru diagnosticul
patologic i stabilirea gradului de difereniere al tumorii. Leziunile au fost clasificate dup cum
urmeaz: CIN1 (neoplazie cervical intraepitealial 1) (n=17), CIN2 (n=11), CIN3 (n=7),
carcinom microinvaziv (n=10) i carcinom invaziv (n=49). Cazurile control (n=5) au fost
reprezentate de specimenele normale rezultate n urma procedurii de biopsie.
Imunohistochimie. Pentru evidenierea macrofagelor, am recurs la coloraia seciunilor cu
anticorpul primar monoclonal anti-CD68, clona PG-M1, RTU, DakoCytomation (Danemarca).
Demascarea antigenului a a fost efectuat prin digestie enzimatic. Sistemul de lucru compatibil
a fost cel de tip LSAB2, iar cromogenul aplicat 3,3 diaminobenzidina dihidroclorid, vizualizat
printr-o reacie de culoare brun. Nucleii au fost colorai cu hematoxilin Lille modificat.
Montarea s-a realizat n mediu de montare permanent (balsam de Canada). ntreaga procedur
imunohistochimic a fost executat cu ajutorul DakoCytomation Autostainer. Drept control
pozitiv intern au fost considerate macrofagele CD-68 pozitive.
Metoda de cuantificare hot spot. este cea mai utilizat metod manual de cuantificare a
structurilor histologice. La microscopul optic ariile de cuantificare se aleg la o mrire 200, ceea
ce corespunde suprafeii de 0,74 mm2. Metoda const n alegerea a trei zone cu densitatea cea
mai mare a macrofagelor, numrarea fiind urmat de calcularea mediei aritmetice.
Analiza statistic. A fost efectuat cu programul SPSS13-0, i a inclus testul Chi ptrat i
testul Student, valorile p<0.05, fiind considerate semnificative.
Rezultate
Specificitatea imunocolorrii anti-CD68. Produsul final de reacie pentru CD36,
macrofagele, s-au colorat n brun cu DAB. Reacia a fost exprimat la nivelul citoplasmei cu
pattern difuz.
Distribuia macrofagelor CD68 pozitive n cervixul uterin normal. n specimenele normale
macrofagele erau prezente n stroma subepitelial, mai ales n profunzimea ei, fiind mai puine n
epiteliul stratificat scuamos (Tab. 1). Numrul macrofagelor CD68 pozitive sporea n cazul
infiltratelor limfo-histiocitare subepiteliale.
Macrofagele CD68 pozitive n leziunile precursoare. n CIN1, distribuia macrofagelor
CD68 pozitive nu se deosebea de cervixul uterin normal, se constata doar o uoar cretere a
densitii acestora. n CIN2, numrul macrofagelor era mai mare, mai ales pe contul infiltrrii
33

epiteliului neoplazic (Tab. 1). Macrofagele intraepiteliale CD68 pozitive erau de dimensiuni mai
mari i infiltrau toate straturile epiteliului scuamos, fiind mai puine totui n stratul superficial.
n strom, macrofagele CD68 pozitive erau localizate mai frecvent la interfaa cu epiteliul
stratificat scuamos, adernd intim la membrana bazal a acestuia, de asemenea n apropierea
vaselor sanguine. O distribuie similar a macrofagelor a fost observat i n cazurile cu CIN3,
doar c a fost observat o cretere a densitii macrofagelor CD68 pozitive n profunzimea
epiteliului neoplazic (Tab. 1-3).
Tabelul 1
Densitatea macrofagelor CD68+ intra- i periepiteliale n cadrul progresiei
neoplaziei de col uterin

Macrofage CD68+
periepiteliale
Macrofage CD68+
intraepiteliale

Cazuri
control
(norm)
106,64,9
n=5
51,25,1
n=5

CIN1

CIN2

CIN3

118,95,5
n=17
56,53,6
n=17

125,88,8
n=11
78,55,2
n=11

123,012,1
n=7
104,08,0
n=7

Carcinom
microinvaziv
309,121,1
n=10
207,117,8
n=10

Carcinom
invaziv
405,111,3
n=49
194,36,4
n=49

Tabelul 2
Compararea densitii macrofagelor intraepiteliale CD68+ dintre cazurile control, CIN1-3,
carcinom microinvaziv scuamocelular i carcinom invaziv scuamocelular al colului uterin
Diagnosticul histologic
Control, CIN1
Control, CIN2
Control, CIN3
Control, Carcinom microinvaziv
Control, Carcinom invaziv
CIN1, CIN2
CIN1, CIN3
CIN1, Carcinom microinvaziv
CIN1, Carcinom invaziv
CIN2, CIN3
CIN2, Carcinom microinvaziv
CIN2, Carcinom invaziv
CIN3, Carcinom microinvaziv
CIN3, Carcinom invaziv
Carcinom microinvaziv, Carcinom invaziv

t
2,19
9,84
13,94
25,71
58,37
12,16
15,08
26,48
109,56
7,49
22,04
63,66
16,15
28,60
2,25

p
<0.05
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.05

Macrofagele CD68 pozitive n carcinoamele microinvazive i invazive. n cazurile cu

carcinoame microinvazive, densitatea macrofagelor CD68 pozitive cretea vertiginos (Tab. 1-3)
att n epiteliul neoplazic, ct i n stroma conjunctiv. Cele mai multe macrofage CD68 pozitive
au fost prezente n aria de invazie a carcinomului, unde aceste celule erau mai voluminoase, de
asemenea ocazional se ntlneau macrofage multinucleate. Macrofagele CD68 pozitive erau
localizate n stroma peritumoral, n imediata apropiere de vasele patului microcirculator, plajele
tumorale i, foarte frecvent, chiar n insulele de celule tumorale. Numrul de macrofage CD68
pozitive era maximal n cazurile cu carcinoame scuamocelulare invazive (Tab. 1-3). n aceste
cazuri, macrofagele erau omniprezente fiind localizate n stroma peritumoral, n insulele de
celule tumorale, n infiltratele inflamatorii, n zonele de necroz a tumorii, n jurul vaselor
sanguine i limfatice din ariile peritumorale.
34

n 16 din 49 cazuri studiate cu carcinoame scuamocelulare invazive au fost observate

macrofage multinucleate gigantice. Remarcm faptul, ca astfel de structuri au fost ntlnite, n
exclusivitate, n interiorul insulelor de celule tumorale.
Tabelul 3
Compararea densitii macrofagelor periepiteliale CD68+ dintre cazurile control, CIN1-3,
carcinom microinvaziv scuamocelular i carcinom invaziv scuamocelular al colului uterin
Diagnosticul histologic
t
Control, CIN1
4,78
Control, CIN2
5,59
Control, CIN3
3,23
Control, Carcinom microinvaziv
28,76
Control, Carcinom invaziv
109,27
CIN1, CIN2
2,35
CIN1, CIN3
0,87
CIN1, Carcinom microinvaziv
27,91
CIN1, Carcinom invaziv
137,14
CIN2, CIN3
0,53
CIN2, Carcinom microinvaziv
25,49
CIN2, Carcinom invaziv
90,15
CIN3, Carcinom microinvaziv
22,97
CIN3, Carcinom invaziv
58,14
Carcinom microinvaziv, Carcinom invaziv
13,96
* ntre grupele comparate nu au fost stabilite deosebiri veridice

p
<0.001
<0.001
<0.01
<0.001
<0.001
<0.05
1*
<0.001
<0.001
1*
<0.001
<0.001
<0.001
<0.001
<0.001

Discuii
Componentul inflamator al neoplaziei include o populaie celular divers: macrofage,
limfocite, neutrofile, eozinofile i mastocite. Infiltrarea leucocitelor n focarul neoplazic poate fi
privit sub aspect de rspuns antitumoral. Exist, ins, multe studii convingtoare care pun n
eviden c limfocitele i macrofagele recrutare din patul microcirculator n focarul neoplazic
reprezint sursa major de citokine proinflamatorii, factori de proliferare i factori angiogenici.
Compoziia, distribuia i numrul limfocitelor ce infiltreaz tumoarea pot avea impact asupra
diagnosticului, pronosticului i tratamentul pacienilor cu maladie oncologic.
Macrofagele, prin prisma spectrului su funcional, sunt celule universale ale organismului,
cu o vdit heterogenitate. Aceast heterogenitate apare n timpul diferenierii lor din precursorii
monocitari i este determinat de stimuli genetici, tisulari, imuni. n aceast ordine de idei,
antigenele microbiene, produii tumorali, complexele imune influeneaz heterogenitatea i
statutul de activare al acestor celule. Sub aciunea moleculelor microbiene, celulelor canceroase,
citokinelor
macrofagele
rspund
prin
sinteza
substanelor
proinflamatorii/microbicide/tumoricide. Acest rspuns poart denumirea de activare clasic i
se realizeaz cnd asupra lor acioneaz interferonul- (IFN), TNF, acidul lipotecoic,
proteinele ocului hipertermic, componentele ECM. Macrofagele rezultate n urma activrii
clasice (M1) i produii lor joac un rol important n aprarea contra patogenilor intracelulari, iar
n anumite condiii i contra celulelor tumorale. M1, de obicei, produc cantiti mari de IL-12 i
IL-23 i cantiti mici de IL-10. De asemenea sunt promotori puternici ai rspunsului imun TH1
mediat (Limfocitele T-helper subgrupa 1), manifest o activitate antiproliferativ i citotoxic,
datorit abilitii lor de a secreta compui azotai reactivi, NO, peroxid de hidrogen, superoxid,
ct i citokinelor proinflamatorii (TNF, IL-1, IL-6) [11].
Datele noastre vin s confirme multe alte studii similare vis-a-vis de distribuia TAM.
TAM se situeaz sub membrana bazal a epiteliului neoplazic, n zona de invazie tumoral, n
jurul vaselor microcirculaiei, n ariile stromale hipoxice i perinecrotice a tumorii. De rnd cu
35

fibroblastele TAM sunt apte de a secreta intens MMP [14], respectiv de a degrada matricea
extracelular (ECM) n cadrul invaziei tumorale. Hipoxia inhib migrarea macrofagelor, astfel
TAM sunt imobilizate n ariile hipooxigenate ale tumorii [6]. Hipoxia supreseaz activitatea
antitumoral a TAM, abilitatea de a fagocita celulele moarte i a prezenta antigenul limfocitelor
T, reduc sinteza a TNF- [8]. Migrarea TAM n zonele hipoxice/necrotice este extrem de
important pentru supravieuirea celulelor tumorale, care au nevoie de vacularizare.
Cele expuse mai sus pledeaz n mod evident pentru implicarea TAM n angiogeneza
tumoral-indus prin formarea vaselor sangvine noi i remodelarea lor ulterioar ntr-o reea
vascular funcional. Fiind recrutate din sngele periferic, TAM migreaz n zonele de hipoxie a
tumorii, unde este nevoie acut de o reea vascular pentru supravieuirea celulelor tumorale,
fiind aici activate de ctre factorii de semnalizare locali. n urma activrii, la care sunt supuse,
macrofagele recrutate se difereniaz spre un fenotip polarizant ce sintetizeaz intens factori
proangiogeni. Acest lucru contribuie la formarea vaselor sangvine noi, fapt ce va determina
creterea local a tumorii i supravieuirea celulelor canceroase. Mai mult, sunt date despre
implicarea TAM i n procesul de limfogenez tumoral [13].
O perioad ndelungat de timp prezena macrofagelor n zona tumoral i peritumoral a
fost interpretat drept un rspuns adecvat al organismului gazd la tumoarea n cretere, aceast
prezen fiind considerat o ncercare a organismului de a inhiba procesul tumoral. Cu timpul,
ns, a devenit tot mai clar c TAM sunt nite actori activi n progresia tumorii i rspndirea
celulelor neoplazice. Studiile experimentale i preclinice au fost susinute de un numr mare de
studii clinice, care au gsit corelaii semnificative ntre densitatea macrofagal crescut i
prognosticul prost. TAM favorizeaz progresia tumorii prin multiple mecanisme: creterea
tumorii, invazie, imunosupresie i supravieuirea celulelor neoplazice, remodelarea stromal,
angiogenez, limfangiogenez, metastazare. Datorit acestei implicri multicomponente n
procesul de progresie TAM au devenit o int terapeutic atractiv. Au fost identificate 3 verigi
patogenetice de perspectiv, asupra crora s se influeneze medicamentos: 1) inhibiia recrutrii
lor n zona leziunii; 2) inhibiia efectului lor proangiogen i remodelrii stromale; 3) reversia
imunosupresiei cu restabilirea abilitilor sale citotoxice antitumorale.
Concluzii
1. Densitatea macrofagelor CD68 pozitive sporete pe msura progresiei neoplaziei de col
uterin, atingnd valori maxime n cu carcinoame scuamocelulare franc invazive.
2. Macrofagele CD68 pozitive sunt omniprezente n epiteliul neoplazic, unde au dimensiuni mai
mari i pot fi multinucleate.

1.

2.
3.
4.
5.
6.

7.

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PROLIFERAREA LIMFOVASCULAR N NEOPLAZIA SCUAMOCELULAR DE CERVIX UTERIN

Vitalie Mazuru, Veaceslav Fulga, Oxana Mazuru, Tatiana Globa, Lilian aptefrai
Catedra Histologie, Citologie i Embriologie
Summary
Limphovascular proliferation within the squamous cell neoplasia of uterine cervix
The aim of this research was the study of proliferative lymphatics microvascular density in
preneoplastic and neoplastic lesions of uterine cervix. Material: squamous metaplasia (n=22)
cases, CIN I (n=16), CIN II (n=14), CIN III (n=6), microinvasive carcinoma (n=15),
invasive carcinoma (n=32). Methods: for histopathologic diagnosis and lesions stadialisation
hematoxilin&eosin staining has been used. For identification of general LMVD and density of
proliferative lymphatics the LSAB+/HRP Double Stain technique were performed. Two
monoclonal antibodies have been used: anti D2-40 and anti Ki-67. Weidner hot spot modified
method was used for lymphatic vessels quantification. Results: proliferative lymphatic vessels
density in squamous metaplasia was equal with 0,93; CIN I 1,4; CIN II 3,33; CIN III 4,56;
microinvasive carcinoma 3,01; invasive carcinoma 2,14. Intratumoral lymphatics were small,
flattened, without lumen. Peritumoral lymphatics were large, with distinct lumen. In peritumoral
area were found 21 lymphatic vessels with tumor emboli inside, 8 of them were proliferative
lymphatics. Conclusions: preneoplastic and neoplastic lesions of uterine cervix determine active
formation of new lymphatic vessels. Lymphangiogenic switch begins in CIN I stage. In CIN III
stage the LMVD is the highest. The intensity of tumor lymphangiogenesis is not smaller than in
CIN stages. The spreading of tumor cells occurs through both types of lymphatic vessels:
preexisting and newly formed.
37

Rezumat
Scopul lucrrii a fost studierea densitii microvasculare limfatice proliferante n leziunile
preneoplazice i neoplazice de cervix uterin. Material: metaplazie scuamoas (n=22) cazuri,
CIN I (n=14), CIN II (n=12), CIN III (n=6), carcinom microinvaziv (n=15), carcinom
invaziv (n=32). Metode: hematoxilin i eozin pentru diagnosticul histopatologic i
stadializarea leziunilor; dubl imunocolorare utiliznd tehnica LSAB+/HRP Double Stain. Au
fost utilizai pentru cercetare anti D2-40 i anti Ki-67. Numrarea vaselor limfatice s-a fcut prin
metoda hot spot modificat a lui Weidner. Rezultate: densitatea vaselor limfatice proliferante n
metaplazia scuamoas este egal cu 0,93; CIN I 1,4; CIN II 3,33; CIN III 4,56; carcinom
microinvaziv 3,01; carcinom invaziv 2,14. Limfaticele intratumorale au fost mici, colabate,
iar cele peritumorale medii sau mari, cu lumen evident. Au fost depistate 8 vase limfatice
proliferante cu emboli tumorali n lumen. Concluzii: leziunile preneoplazice i neoplazice
determin activ formarea limfaticelor de neoformaie, switch-ul limfangiogen ncepe n CIN I i
atinge apogeul n CIN III. Intensitatea limfangiogenezei tumorale n carcinoamele invazive nu
este mai mic dect n CIN. Metastazarea celulelor neoplazice are loc att prin limfaticele
preexistente, ct i prin cele de neoformaie.
Actualitatea
Carcinomul de cervix uterin reprezint una din cele mai frecvente afeciuni maligne umane.
Pe parcursul ultimelor decenii a fost demonstrat caracterul evident infecios a acestei maladii.
Este cunoscut nu numai agentul etiologic (papilomavirusul uman), dar i serotipurile cu potenial
cancerigen marcat, a fost introdus n practica medical vaccinarea mpotriva acestui agent.
Aceste evenimente au avut drept efect micorarea dramatic a incidenei neoplaziei de cervix
uterin. Exist, ns, regiuni cum ar fi Africa ecuatorial (Uganda, Rwanda), America Central
(Mexic, Honduras, Costa Rica), America de Sud (Columbia, Bolivia, Brazilia, Peru), rile
Europei de Sud-est, n care morbiditatea i mortalitatea prin carcinomul de col uterin ocup
poziii de top n patologia oncologic[1]. Astfel, este absolut firesc interesul fa de aceast
afeciune n rndul cercettorilor de specialitate.
Pe parcursul ultimelor decenii a fost demonstrat faptul, c pentru progresia tumoral au
importan nu numai evenimentele ce se petrec n celulele tumorale (indiferent de tumor), ci i
care au loc n stroma intratumoral i peritumoral. Este bine cunoscut faptul c orice tumoare, la
etapa iniial de dezvoltare, i satisface necesitile nutritive, plastice i respiratorii din contul
reelei vasculare preexistente. Pe parcursul creterii, intervine un moment critic, cnd aceste
necesiti nu mai pot fi acoperite de ctre reeaua vascular preexistent. n acest moment
tumoarea i celulele stromei (celulele rezidente, celulele inflamatorii recrutate din sngele
periferic) ncep o colaborare coordonat n vederea formrii unei reele vasculare noi[2] prin
remodelarea stromal i sinteza factorilor de cretere (mitogeni pentru endoteliul att vascular,
ct i limfatic). Angiogeneza tumoral a fost studiat cu lux de amnunte. Se cunosc bine
circumstanele, mecanismele moleculare i consecinele acestui fenomen. n schimb, fenomenul
de formare al vaselor limfatice, sub aciunea tumorii, este mult mai puin studiat.
Limfangiogeneza tumoral este un fenomen biopatologic ce decurge paralel sau secundar
angiogenezei [3]. Este bine cunoscut faptul c tumorile solide metastazeaz prin cteva ci: per
continuam, prin vasele sangvine i prin cele limfatice. Rspndirea celulelor neoplazice pe cale
limfatic este calea primar de metastazare pentru un ir de neoplazii cum ar fi: carcinomul
cervical, ovarian, mamar, gastric, pulmonar[4]. n rezultatul acestei metastazri sunt implicai n
proces ganglionii limfatici regionali, aspect care coreleaz cu nrutirea prognosticului de
supravieuire la pacienii respectivi[5]. Descoperirea marcherilor specifici pentru endoteliul
limfatic a constituit un salt important n studiul limfangiogenezei fiziologice i tumorale. Una din
ntrebrile la care nu exist un rspuns echivoc pn n prezent este originea vaselor limfatice
prin intermediul crora are loc metastazarea celulelor neoplazice: prin vasele limfatice
preexistente sau prin reeaua vascular limfatic format de tumor[6].
38

Scopul
Reieind din cele expuse, scopul lucrrii, a fost studiul limfangiogenezei n leziunile
colului uterin prin depistarea proliferrii endoteliocitelor limfatice cu ajutorul anticorpului
monoclonal anti Ki-67.
Material i metode
Au fost supuse studiului specimenele obinute prin biopsii intite i conizaie de la
pacientele cu leziuni macroscopic decelabile. Materialul biologic a fost fixat n soluie de formol
tamponat. Dup splarea n ap de robinet, dehidratarea n soluii descrescnde de alcool i
clarefierea n soluie de xilen, specimenele au fost incluzionate n parafin. ntreaga prelucrare
preliminar a materialului a fost efectuat n conformitate cu prevederile tehnicii histologice
convenionale. Seciunile, cu grosimea de 3mkm, au fost fcute la microtomul de tip sliding
ERMA Japan. Diagnosticul histopatologic i gradarea leziunilor au fost efectuate prin colorarea
cu hematoxilin i eozin. Au fost identificate urmtoarele tipuri de leziuni: metaplazie
scuamoas (n=22), CIN I (n=14), CIN II (n=12), CIN III (n=6), carcinom microinvaziv (n=15) i
carcinom invaziv (n=32). Am efectuat dubl imunocolorare a seciunilor, utiliznd 2 anticorpi
monoclonali: anti Ki-67 clona MIB1 Dako Cytomation (Carpinteria, CA, USA) i anti D2-40
clona D2-40 DakoCytomation (Danemarca). Anti Ki-67 a fost utilizat pentru evidenierea
endoteliocitelor limfatice proliferante, iar anti D2-40 pentru a pune n eviden vasele limfatice
i, astfel, de a diferenia anume endoteliul limfaticelor pozitiv la anti Ki-67 de alte elemente
celulare ale tumorii aflate n proliferare (Ex endoteliul vaselor sangvine). Tehnica
imunohistochimic utilizat a fost LSAB+/HRP Double Stain. Demascarea antigenic s-a fcut n
soluie Target Retrieval pH6, la temperatura 97oC, timp de 20 minute. Primul anticorp aplicat a
fost anti D2-40, cu timpul de incubare 30 minute, apoi s-a aplicat sistemul avidin-biotin HRP, iar
vizalizarea s-a fcut cu 3,3'-diaminobenzidin (DAB) n calitate de cromogen. Al doilea anticorp
aplicat a fost anti Ki-67 cu perioada de incubare 30 minute. Dup aplicarea sistemului avidinbiotin HRP, vizualizarea s-a fcut cu cromogenul amino-etilcarbazol (AEC). Pentru
contracolorarea nucleilor a fost utilizat hematoxilina Lille modificat. Specimenele histologice
colorate imunohistochimic au fost montate n mediu apos. Procedura de imunocolorare a fost
efectuat cu ajutorul DakoCytomation Autostainer. Examinarea lamelor histologice s-a fcut la
microscopul Nikon Eclipse E600.
Cuantificarea densitii microvasculare limfatice (LMVD) s-a efectuat n conformitate cu
metoda modificat a cmpurilor fierbini (hot spot) a lui Weidner[7]. Ea const n examinarea, la
amplificarea X200, a trei cmpuri de strom localizate n imediata vecintate a neoplaziei sau a
epiteliului normal, n care expresia anticorpului mai puternic exprim. Suma primit n rezultatul
identificrii structurilor int se mparte la 3, iar media aritmetic obinut este rezultatul final al
examinrii unui caz. Au fost numrate doar acele vase limfatice, pozitive la D2-40, la care s-a
depistat cel puin o celul endotelial Ki-67 pozitiv.
Rezultate
LMVD Ki-67 pozitive n metaplaziile scuamoase. n 8 cazuri nu a fost depistat nici un vas
limfatic (VL) cu endoteliocite proliferante. Densitatea maximal a fost de 2,8 VL, valoarea
medie fiind de 0,93 VL.
LMVD Ki-67 pozitive n leziunile preneoplazice. S-a constatat o cretere stabil a
numrului de VL proliferante o dat cu progresia gradului de leziune intraepitelial. n CIN I
numrul VL cu endoteliocite proliferante a variat ntre 0 (n 2 cazuri) i 2,4. Media a fost de 1,4.
n CIN II rezultatele au variat ntre 0 (ntr-un singur caz) i 3,8. Media a constituit 3,33 VL. n
CIN III, n toate cazurile au fost detectate VL Ki-67 pozitive. Densitatea lor a variat ntre 4 i 5,2
cu medie de 4,56. E de menionat faptul c n leziunile intraepiteliale de grad nalt (CIN II i mai
ales CIN III) vasele limfatice se depistau deja nu numai n stroma profund, dar i n imediata
vecintate cu membrana bazal a epiteliului exocervical. Majoritatea VL Ki-67 pozitive aveau un
lumen bine definit (erau perfuzabile).
39

LMVD Ki-67 pozitive n carcinoamele microinvazive i invazive. n carcinoamele

scuamocelulare microinvazive i frank invazive, densitatea microvascular a VL D2-40 pozitive,
i a VL proliferante (Ki-67 pozitive) scade. Cu ct este mai avansat procesul tumoral, cu att
mai mic este aceast densitate. n carcinoamele microinvazive numrul de VL Ki-67+ a variat
ntre 0 (un caz) i 5,2 (media 3,01). n cele invazive, numrul vaselor limfatice a fost ntre 0 (2
cazuri) i 3,4 (media 2,14). Mjoritatea VL proliferante erau localizate n stroma peritumoral,
VL intratumorale Ki-67 pozitive constituind aproximativ din toate vasele identificate.
Limfatice intratumorale, indiferent de statutul lor de proliferare, erau non-funcionale, avnd o
structur aplatisat, sinuoas, lipsite de lumen. VL din zona peritumoral erau mari, perfuzabile,
cu un lumen evident. Majoritatea VL proliferante aveau lumen mediu, mult mai rar, lumen
lumen mare. Remarcm faptul, c embolii tumorali au fost depistai att n limfaticele neactivate,
ct i n cele activate (Ki-67 pozitive).
Tabelul 1
Densitatea vaselor limfatice Ki-67 pozitive n leziunile preneoplazice i
neoplazice ale colului uterin
Tipul leziunii
Nr. total de
Valoarea
Valoarea
Valoarea
cazuti
minim
maxim
medie
22
0
2,8
Metaplazia
0,93
scuamoas
14
0
2,4
CIN I
1,4
12
0
3,8
CIN II
3,33
6
4
5,2
CIN III
4,56
15
0
5,2
Carcinom
3,01
microinvaziv
32
0
3,4
Carcinom invaziv
2,14
Discuii
Importana sistemului vascular limfatic n rspndirea la distan a celulelor tumorale este
bine cunoscut. Exist o serie de tumori solide la care calea limfatic de metastazare este cea
primar[8]. Prin intermediul acestei ci are loc afectarea metastatic a ganglionilor limfatici
regionali. Acest fapt are o importan major n evoluia ulterioar a neoplaziei, n tratamentul
antitumoral i asupra termenului de supravieuire al pacienilor. Implicarea n proces a
ganglionilor limfatici coreleaz cu un pronostic nefavorabil.
Apariia markerilor specifici pentru endoteliului limfatic a fcut posibil elucidarea
mecanismelor moleculare ale limfangiogenezei, mai ales n cazul limfangiogenezei tumorale. n
pofida succeselor marcate obinute pe parcursul ultimelor dou decenii, mai exist nc o serie de
ntrebri ce planeaz asupra acestui fenomen asociat proceselor tumorale.
Au fost efectuate mai multe cercetri axate pe studiul LMVD cu ajutorul diferitor markeri
specifici cum ar fi: LYVE-1[9], VEGFR3[10], Prox-1 [11]. n baza rezultatelor obinete a fost
stabilit faptul c tumorile determin formarea unei reele limfovasculare din vasele preexistente.
Switch-ul limfangiogenic (formarea masiv a VL, dictat de tumoare), n neoplaziile
scuamocelulare de cap i gt, ale cavitii bucale, esofagiene i cervicale ncepe la stadiul de
leziune intraepitelial CIN I i i atinge apogeul n stadiul de CIN III [12]. Densitatea VL n
leziunile preneoplazice a fost corelat i cu gradul de expresie al VEGFC[13] - mitogen foarte
puternic i specific al endoteliul limfatic. Densitatea VL, odat cu momentul invaziei tumorale,
ncepe s descreasc. Acest fenomen poate fi explicat prin liza proteolitic a VL de ctre celulele
neoplazice din frontul invaziv al tumorii. VL aflate iniial la periferia tumorii, ulterior, o dat cu
creterea ei n volum, sunt racolate n aria plajei tumorale[14].Rezultatele noastre vin s
confirme acest lucru i n cazul neoplaziei de cervix uterin. Este evident c VL intratumorale
sunt limfatice de neoformaie, pe cnd cele peritumorale au o origine mai mult sau mai puin
obscur. Cu toate c studiile LMVD cu markeri specifici pentru endoteliului limfatic indic o
cretere evident a densitii microvasculare n progresia neoplaziilor cervicale, densitatea VL
40

rmne totui un indiciu indirect, de constatare, al neoformrii acestor vase. Din aceast cauz
am decis s studiem densitatea vaselor limfatice proliferante, utiliznd markerul proliferrii
nucleare Ki-67.
Ki-67 este o protein nuclear, care se exprim preferenial pe parcursul fazelor active ale
ciclului celular (G1, S, G2 i M), dar nu se expreseaz n celulele aflate n G0[15]. n interfaz,
antigenul este depistat exclusiv n nucleu, n timp ce pe parcursul mitozei markerul se localizeaz
pe suprafaa cromozomilor. n celulele ce intr n faza non-proliferativ, antigenul este rapid
supus degradrii[16].
Rezultatele acestei cercetri indic faptul, c pe parcursul evoluiei neoplaziei de col col
uterin are loc formarea de VL tumoral-derivate. Rata limfaticelor proliferante are o dinamic
comparabil cu densitatea general de vase limfatice, curbele lor de cretere i descretere fiind
identic.
Marea majoritate a studiilor axate pe morfologia VL din zonele intratumoral i
peritumoral pledeaz pentru ideea c limfaticele din plaja tumorii nu sunt funcionale[17; 18],
rolul n rspndirea celulelor neoplazice revenind limfaticelor de la periferia tumorii[19]. Totui
exist date, foarte puine, despre unele tumori n care limfaticele intratumorale sunt
funcionale[20]. Aceste rezultate stau la baza conceptului conform cruia anume limfaticele
peritumorale asigur rspndirea celulelor neoplazice pe cale limfovascular. Rezultatele noastre
confirm aceste date. n carcinoamele invazive, limfaticele intratumorale, att VL D2-40+, ct i
Ki-67+ sunt mici i colabate, lipsite de lumen. Limfaticele din aria peritumoral, ns, sunt medii
sau mari cu un lumen evident. Mai mult, au fost depistate VL cu emboli tumorali doar n ariile
peritumorale. Prezena embolilor tumorali i n limfaticele activate indic faptul c, n
carcinoamele cervicale invazive, sunt implicate n metastazarea limfovascular att limfaticele
preexistente, ct i cele de neoformaie.
Concluzii
Limfangiogeneza tumoral este unul din evenimentele cheie care se produce n cadrul
progresiei neoplaziei de col uterin. n baza rezultatelor despre densitatea microvascular
limfatic general, dar mai ales cea proliferant, corelat la stadiul de progresie al leziunii
cervicale am constatat c debutul formrii de vase limfatice, condiionat de leziune, ncepe la
nivelul de CIN I i crete progresiv, atingnd apogeul su la nivelul de CIN III. O dat cu
apariia invaziei densitatea limfaticelor scade, ajungnd n carcinoamele frank invazive s fie la
un nivel comparabil cu nivelul LMVD din CIN II. Acest aspect denot faptul c pe parcursul
evoluiei neoplaziei cervicale are loc formarea unei reele vasculare limfatice de neoformaie. n
opinia noastr, datorit faptului c raportul LMVD general/LMVD proliferant rmne acelai, n
carcinoamele invazive are loc o limfangiogenez tumoral tot att de intens ca i n leziunile
preneoplazice, chiar dac densitatea VL este simitor n descretere. Prezena embolilor tumorali
i n interiorul VL proliferante ne face s concluzionm c metastazarea limfovascular n
carcinoamele cervicale invazive are loc att prin limfaticele preexistente, ct i prin cele aprute
n rezultatul limfangiogenezei tumorale.
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42

CELULELE MESENCHIMALE STEM ALE COMPLEXULUI OMBELICOPLACENTAR: NECESITATE I UTILITATE

Lilian Globa
USMF Nicolae Testemianu, Laborator al Ingineriei tisular i culturi celulare
Summary
The mezenchimal stem cells of umbilical placental complex: utility and necessity
This research concludes the last performances in the cell transplantation domain. There
are exposed the most relevant areas of utility of the mezenchimal stem cells, especially as cell
graft. There is also mentioned the history of development of this mezenchimal stem cells for
transplant from different sources and the perspective of their use from the umbilical placental
complex.
Rezumat
Lucrarea reflect performanele n domeniul transplantologiei celulare. Sunt expuse
domeniile cele mai importante de utilizare a celulelor mezenchimale stem, n special ca gref
celular. De asemenea se menioneaz istoricul de folosire a celulelor mezenchimale stem de
diferite origini i perspectiva utilizrii lor din complexul ombilico placentar.
Complexul Ombilico - Placentar (COP) alctuit din structurile (organele) provizorii sau
temporare, care dezvoltndu-se n procesul embriogenezei n afara embrionului, realizeaz o
mulime de funcii ce asigur creterea i dezvoltarea embrionului. COP se refer: Amnionul,
Corionul, Sacul vitelin, Alantoida, Cordonul Ombilical i Placenta.
n prezent aceste structuri ale COP sunt n centrul ateniei comunitii tiinifice, fiind
foarte intens studiate n special n privina separriii, prezervrii i multiplicrii celulelor stem
hematopoietice i mezenchimale (MSC), acelor celule multipotente capabile s dea natere
diferitor tipuri de tulpini celulare. (1-4)
n ultima perioad, a luat o amploare mare studierea celulelor pluripotente (stem) n
privina utilizrii lor ca grefe celulare pentru transplantare alogen i autogen n zonele cu
deficit de regenerare (posttraumatice, ischemice, defecte tisulare etc), un compartiment separat
fiind atribuit componentelor COP.
Celulele mezenchimale stem (MSC) sunt cunoscute ca celule medulare stromale (5) sau
celule progenitoare mesenchimale (6) sunt definite ca celule progenitoare multipotente ce se
autorenoiesc cu o capacitate de difereniere ntr-o serie de linii celulare: esut conjunctiv
scheletal (osos, cartilaginos, strom reticular a mduvei osoase roii, adipocite) (7,8), sunt date
care sugereaz c MSC pot da natere muchiului striat cardiac i scheletic (9-11), celulelor
endoteliale (12), i chiar celulelor de origine non mesodermal: ca hepatocitelor (13), celulelor
sistemului nervos (neuroni i neurogliei) (14), celulelor epiteliale (15,16). Astfel termenul de
pluripotent i multipotent sunt reciproc utilizate n descrierea capacitii de difereniere a MSC
ntr-un spectru foarte larg de esuturi.(17)
Iniial MSC au fost identificate n mduva roie osoas i apoi n esutul muscular,
adipos i conjunctiv (18-21). Capacitatea de difereniere a MSC scade dramatic cu creterea
vrstei (22). De acea s-au cutat alte surse alternative de MSC, care au urmat: lichidul amniotic,
placenta sngele ombilical, venele ombilicale, esutul conjunctiv al cordonului ombilical (23-25),
mezenchima pulpar a dinilor deciduali.
De asemenea au fost studiate i structurile fetale ca surse de MSC, astfel n perioada
mijlocie de gestaie s-au obinut grefe din splin, pulmoni, pancreas, rinichi (26-31). Unii autori
confirm c MSC sunt afiliate vaselor, fiind amplasate perivascular constituie un depou de MSC
ce se extinde prin tot organismul i activez cu rol de reparator tisular, stabilizeaz vasele
sangvine i menin homeostazia tisular (32-37).
Avnd ca avantaj lipsa problemelor etice MSC se plaseaz ca cei mai promitori
candidaii n terapia celular, bioinginerie i terapii cu celule stem pentru multe boli umane
43

severe. Deoarece cercettorii din diverse ri i domenii utilizau diferite metode de evideniere,
izolare sau cultivare, s-a fondat Comitetul celulelor MSC a Societii Internaionale pentru
terapia celular. Acesta a propus criterii minime pentru definirea MSC umane: primul criteriu
s se menin aderent pe suporturile de cultivare; al doilea s exprime pe suprafa antigenii
CD105, CD73 i CD90 i s nu exprime CD45, CD34, CD14 ori CD11b, CD79a ori CD19,
HLA-DR; al treilea rnd necesit s aib capacitatea de a se diferenia n vitro n osteoblaste,
chondroblaste i adipocite (38, 39).
Celulele MSC din complesul ombilico placentar sunt mai avantajate dect cele din
mduva osoas deoarece:
Sunt uor de prelevat, conservat (congelat) i utilizat (clinic, manipulaii genetice)
Donatorul nu este omul ci componenta extraembrionar
Au compatibilitate imun ridicat, HLA antigen este absent sau slab evideniat
Se pot stoca pentru a forma bnci de celule stem proprii
Foarte intens pn n present s-a studiat sngele din cordonul umbilical, cu toate c unii
cercettori susin c majoritatea MSC se afl n esuturile complesul ombilico placentar (54).
esutul mucos conjunctiv al cordonului ombilical (jeleul Warton) este cel mai tnr esut
conjunctivcare poate induce formarea, celulelor esutului nervos (neuroni i celule gliale)(54).
Celulele mesenchimale depistate n amnion la fel au un diapazon foarte larg de difereniere
(multipotente) i au fost catalogate ca viitorul medicinii de ctre biserica catolic care
condamn cercetarea utiliznd embrionii.
Toate aciunile legate de celulele stem sunt reglate de legi i acreditate la nivel naional,
precum i internaional.
Mecanismele de aciune ale celulelor mezenchimale stem nu sunt pe deplin elucidate.
Proprietatea MSC de a fi lipsite de HLA antigeni le transform n celule invizibile pentru
celulele sistemului imunitar gazd, n cazul unui transplant alogen. Unele aciuni ale celulelor
stem ar fi c ele induc diferenierea esutului specific n mediul n care a fost transplantat MSC,
reparar micromediului tisular, posed efecte para- i juxtacrine ale factorilor de cretere i a
citochinelor produse de aceste celule sau de reorganizez matricea extracelular.
Utilitatea celulelor stem mesenchimale a fost demonstrat n:
Patologia cardiovascular. Injectarea celulelor stem n zona ischemic cardiac a dus
la diferenierea cardiomiocitelor, celulelor endoteliale i miocitelor. Ca efect n inima cu infarct
miocardic s-a remodelat miocardul i s-au reparat vasele prin neoangiogenez. MSC cu astfel de
aciuni, avea marcherul CD105 ce se preleva din sngele cordonului ombilical, esut adipos i
din mduva osoas (40, 41). Celulele stem i cele progenitoare cardiace rezidente sunt foarte
asemntoare att fenotipic ct i genotipic.
Patologia osoas i cartilaginoas. Sunt aplicate cu succes n tratamentul osteogenezei
imperfecte caracterizat cu fracturi multiple, cauzate de sinteza defect a colagenului tip I (1,
42). MSC fiind inoculate n zonele de reparaie osoas sau cartilaginoas induc activitatea
pericitelor, ca progenitori celulari care au posibiliti modulatorii asupra matricii exracelulare,
potenial de migraie de proliferare, de re-diferenciere. O surs de celule mezenchimale stem
poate fi MSC din in situ microfracturi, esutul de granulaie, esutul adipos adiacent.
Patologia renal. Se ncearc s fie utilizate MSC n boli cu aspect inflamator, imunitar
i autoimunitar. Sunt rezultate mbucurtoare n tratarea patologiei glomerulare i tubulare
renale. (43, 44). Studiile recente pun n eviden sugestia c celulele interstiiale pot fi
considerate ca un depou de celule progenitoare stem mezenchimale extratubulare. Astfel n
patologia renal restabilirea se petrece prin intermediul celulelor mezenchimale stem locale sau
prin inocularea MSC allogene.
Patologia pielii. S-a observat un potenial mare de reparare a esutului cutanat pe
modele animale i la oameni n tratamentului plgilor de origini diverse (45). n timpul
cicatrizrii cutanate se confrunt dou procese de reparaie i antiinflamator.
Ambele sunt
mediate de substanele produse de celulele progenitoare locale, celule stem de provinin a.
Recent sau evideniat ca celule stem mezenchimale - celulele stem ale foliculilor pieloi ai
44

adulilor. Celulele stem ale folicolului pielos sunt o ni de celule progenitoare care duc la
regenerarea prului, glandelor sudoripare, sebacee i a epidermisului.
Patologia nervoas. O mulime de ncercri se fac n terapia patologiilor sistemului
nervos central i periferic. ncepnd cu bolile neurodegenerative periferice i cele din CNS
(boala demielinizant, Huntington, Parkinson), pn la patologii vasculare, ischemice, traume ale
componentelor SNC i SNP. Se observ careva efecte pozitive, benefice n tratarea parezei
infantile (46-48). MSC induc formarea factorului neuronal de cretere edndogen, descrete
apoptoza, reduce nivelul radicalilor liberi, mbuntete conexiunea sinaptic a neuronilor
afectai. Aceste aciuni MSC le promoveaz prin activiti paracrine producnd factori trofici,
care sunt insuficieni n cazul leziunilor nervoase, aceti factori trofici neuronali i gliali induc
regenerarea i supravieuirea neuronilor locali n cazurile de ictus cerebral i maladiile
neurodegenerative.
Patologia pulmonar. n sindromul de disstres respirator acut se observ o reducere
dramatic a esutului pulmonar, ca rezultat al procesului inflamator i de fibrozare. Prin tehnici
de transplant cu celule stem se ncearc stabilizarea esutului pulmonar i chiar remodelarea
acestuia (49,50). Celulele stem mezenchimale promoveaz repararea vascular i regenerarea
epitelial, de asemenea intervine la etapa de modulare a sistemului imunitar.
Diabetul zaharat. Studiile clinice demonstreaz o reducere considerabil a nivelului
glucozei sangvine n diabetul zaharat juvenil tip I, dup utilizarea SMC. Din celule
mezenchimale stem din cordonul ombilical gelul Wharton se formeaz celule productoare de
insulin n insulele formate de novo (51, 52). Mediatorii imunoreglatori sintetizai de ctre SMC
inhib aciunea pro-inflamatorie a citochinelor prezente n inlamaiile post transplant.
Boli autoimune. Multitudinea de nozologii autoimune din diferite sisteme ale
organismului (scleroz multipl, artrit reumatoid, lupus eritematos sistemic) sunt ca rezultat al
activitii imperfecte a sistemului imunitar. Studiile recente arat aciunea imunosupresoare a
SMC n astfel de patologii (53). De asemenea sunt atestate rezultate pozitive n tratamentul
maladiilor autoimune n combinaie cu cele tradiionale, n special cu tehnicile manipulatorii de
selecie a celulelor limfocitare T.
Pentru aceasta n perspectiva noilor tendine tiinifice i aplicative este necesar de a
pune n eviden majoritatea subtilitilor structurare ale complexului ombilical placentar prin
metode morfologice, histochimice i aprecierea posibilitii utilizrii lor n medicina practic.
Dezvoltnd noi metode terapeutice sunt posibile de rezolvat multe probleme de asisten
medical. Transplantarea CMS ntr-un tratament complex va da un beneficiu att pacienilor ct
i economiei. n timp, cu adncirea cunotinelor n domeniul grefrilor celulare cu MSC vor
avansa foarte mult strategiile de tratament ale multor boli n prezent incurabile.
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TEMCELLS2004;22:1330n1337www.StemCells.com

SOME POINTS IN MECHANISM OF LIVER REGENERATION

(REVIEW)
Elena Mocan, Natalia Boaghie, Oleg Slivca, Viorel Nacu
Laboratory of Tissue Engineering and cell cultures
The State Medical and Pharmaceutical University Nicolae Testemitanu
Summary
In a healthy adult liver, only ~1 hepatocyte in 20,000 (0.005%) is in the cell cycle. The
rest are quiescent, in the G0 state. This article is focusing on the early events occurring in liver
after partial damage (chemical or hepatectomy). Understanding of signaling pathways that
allows hepotatocytes to maintain most of their homeostatic functions and important capacity to
complete restitution of lost or damaged tissue will propose new strategies to treat liver disorders.
48

Rezumat
Anumite aspecte a mecanismului regenerrii hepatice (Review)
ntr-un ficat adult sntos numai o hepatocit din 20.000 (0.005%) exist n ciclul celular
in stare de deviziune. Restul sunt pasive n stare G0. Acest articol se axeaz pe evenimentele
anticipate care au loc n ficat, dup deteriorarea parial (chimic sau prin hepatectomie).
nelegerea cilor de semnalizare, prin care hepatocitele permit meninerea capacitilor
homeostatice si funciilor importante pentru restituirea complet a esutului deteriorat sau
pierdut, propune noi strategii pentru tratarea afeciunilor hepatice.
The liver plays a central role in metabolic homeostasis, as it is responsible for the
metabolism, synthesis, storage and redistribution of nutrients, carbohydrates, fats and vitamins.
The liver produces large numbers of serum proteins including albumin and acute-phase proteins,
enzymes and cofactors. Importantly, it is the main detoxifying organ of the body, which removes
wastes and xenobiotics by metabolic conversion and biliary excretion [6, 12, 16, 19].
Liver regeneration has been recognized by scientists for many years and was even
described by the ancient Greeks, who mentioned liver regeneration in the myth of Prometheus.
Having stolen the secret of fire from the gods of Olympus, Prometheus drew down on himself the
anger of Zeus, the ruler of gods and men. Zeus punished Prometheus by chaining him to Mount
Caucasus where he was tormented by an eagle. The eagle preyed on Prometheus liver, which
was renewed as fast as it was devoured (Bulfinchs Mythology) [16].
It is known adult hepatocytes are long lived and normally do not undergo cell division,
they maintain the ability to proliferate in response to toxic injury and infection. After a partial
hepatectomy (removal of a section of the liver), liver cells reenter the cell cycle and replicate
until the liver recovers its lost mass, within a precision of 10% [9, 12, 16, 19]. There is know a
very phenomenal capacity that in liver regeneration does not require the recruitment of liver stem
cells or progenitor cells, but involves replication of the mature functioning liver cells. However,
it was proved the existence of facultative stem cells in the liver which are undifferentiated cells
as typical stem cell and found in the system of bile canals (Hering canals). Its nearest precursors,
oval cells can give rise to several cell lines, including hepatocytes and biliary epithelial cells [9,
16]. The regenerative process is compensatory because the size of the resultant liver is
determined by the demands of the organism, and, once the original mass of the liver has been
reestablished, proliferation stops [1, 11]. The reasons for initiating the regeneration stage, up to
now finally be resolved. One theory suggests that hemodynamic overload, which is subjected to
the remainder of the liver after its resection, activates inducible nitric oxide synthase (iNOS) and
cyclooxygenase-2, which leads to increased production of nitric oxide (NO) and prostaglandins
[9, 13]. It stresses the importance of preserving portal blood flow and the consistency is
maintained by the hepatic arterial buffer response [17].
Although numerous studies have investigated the molecular mechanisms of liver
regeneration, including the roles of cytokines, growth factors, matrix remodeling, and metabolic
signals [3, 7, 9, 15], any basic questions remain. What are the signals that trigger the early events
in the regenerative process? What role plays stem cells in liver regeneration?
Investigators have begun to answer these questions by using molecular and genetic
approaches to identify the important regulatory pathways that control the regenerative process.
There are different models of study the process of liver regeneration. The most important are
model using chemical administration of hepatotoxic chemicals (e.g. carbon tetrachloride) and
surgical model (technique of partial hepatectomy) [6, 9, 19]. Of course the initial response
reactions are different depend of the nature of damage. For example, during the injury to the
tissue results in disruption of capillary vascular networks and extravasation of blood,
accompanied by local release of coagulation factors, platelets, growth factors, etc. [7, 15]. There
is considerable literature suggesting that the early hemodynamic changes after partial
hepatectomy are important of all aspects of liver regeneration. The importance of the
hemodynamic events and the change of relative proportion of portal to arterial blood are the least
49

studied and least understood. The one of theories suggests that hemodynamic overload after the
liver resection activates inducible nitric oxide synthase (iNOS) and cyclooxygenase-2, which
leads to increased production of nitric oxide (NO) and prostaglandins [2, 7, 9, 13]. NO and
prostaglandins sensitize macrophages to the liver secondary inductors of inflammation,
especially to the endotoxin of gram-negative intestinal microflora, whose level in serum after
liver resection increases. It is related to bacterial translocation from the gut due to a violation of
local immunity, changes in the composition of flora and increase its permeability, and with a
decrease in the absolute number of Kupffer cells and inhibition of their function [6, 7, 13].
Sensitized macrophages produce tumor necrosis factor (TNF-), which is a multifunctional
cytokine, transmitting signals through two types of receptors: TNFR-1 (p55) and TNFR-2 (p75)
[5, 15]. It acts as a mediator of acute-phase response in the liver and has a cytotoxic effect by the
amplified DNA synthesis (phase S), reaching a maximum between 24 and 48 hours after
resection. The peak of DNA synthesis of biliary epithelium cells has observed after 36-48 h,
Kupffer and stellate cells - after 48 h and, finally, the endothelial cells of sinusoids - after 96 h of
surgery [11, 14, 16]. The conversion through the phases of the cell cycle is modulated by the
interaction between cyclins, cyclin-dependent kinases and its inhibitors. After 7-10 days after the
hepatectomy the liver regeneration stops [14].
In a healthy adult liver, only ~1 hepatocyte in 20,000 (0.005%) is in the cell cycle [23].
The rest are quiescent, in the G0 state. After partial hepatectomy, hepatocytes reenter the cell
cycle by going from the G0 state to the G1 phase. Cells in the early G1 phase progress, driven by
growth factors, through the G1/S restriction point, after which cells are committed to progress to
mitosis, even in the absence of the G1 growth factors. However, cells in early G1 phase that have
not reached the restriction point can return to quiescence in the absence of growth factors [11,
15, 16]. Fausto and Riehle have considered three subpopulations of hepatocytes: quiescent cells
(Q), primed cells (P), and replicating cells (R) [2]. In the priming phase of liver regeneration,
multiple immediate-early genes such as c-fos and c-jun are induced [11].
Early events occurring in liver after partial hepatectomy
The partial hepatectomy induces rapid induction of more than 100 genes not expressed in
normal liver [11, 15, 19]. These genes relate directly or indirectly to preparative events for the
entry of hepatocytes into the cell cycle. The functions served are several and many of these genes
(e.g., IGFBP1) appear to play an essential role. One of the earliest observed biochemical changes
is increase in activity of urokinase plasminogen activator (uPA) [1, 10]. The relationship
between increase in uPA and the hemodynamic changes discussed above is not clear, but there is
literature documenting increase of uPA in several cell types including endothelial cells following
mechanical stress associated with increased turbulent flow [2, 15]. Urokinase is known to
activate matrix remodeling, seen in most tissues during wound healing and also in liver
regeneration [1].
Overall regulation of extracellular matrix during liver regeneration is a very complex
process, involving metalloproteinases and tissue inhibitors of metalloproteinases (MMP9) [9,
15]. Hepatic extracellular matrix binds many growth factors. Prominent among matrix binding
growth factors in the liver is hepatocyte growth factor (HGF) [8, 15].
A key endpoint of liver regeneration is the restoration of the total number and mass of
hepatocytes, the main functional cells of the liver responsible for delivering most of the hepatic
functions important for body homeostasis. Hepatocytes are the first cells of the liver to enter into
the cell cycle and undergo proliferation, and they produce mitogenic signals for other hepatic cell
types [15-17]. Quiescent hepatocytes in normal liver express a variety of growth factor receptors.
These include receptors for PDGF, VEGF, fibroblast growth factor receptors, c-kit [1, 6, 15].
Many growth factors and cytokines have been implicated in regulating liver regeneration. The
growth factors include hepatocyte growth factor (HGF), epidermal growth factor (EGF),
transforming growth factors (TGFs), insulin and glucagons. And the cytokines include tumour
necrosis factor TNF and interleukin IL-6. There are several individual transcription factors or
50

proteins that are required for normal liver regeneration but have not yet been associated with
specific growth-factor- or cytokine-regulated signal-transduction pathways [3, 6, 8, 15].
The studies with hepatocytes in primary culture however have shown that despite the
expression of many mitogenic receptors, the only mitogens for hepatocytes in chemically defined
serum-free media are HGF and ligands of the EGFR (EGF, TGF, amphiregulin, HBEGF, etc).
These ligands are direct mitogens [9,15].
Hepatocyte growth factor (HGF)
The view of HGF as an initiator of liver regeneration is bolstered by the fact that it is a
direct mitogen for hepatocytes, it activates its receptor very early, and it can induce most of the
changes occurring during the liver regeneration (including massive hepatic enlargement). HGF
levels in plasma increase 10- to 20-fold after hepatectomy [9, 15]. HGF injection in portal vein
of normal rats and mice causes proliferation of hepatocytes and enlargement of the liver [10, 11].
HGF in liver is produced predominantly by the stellate cells [15], but also by hepatic endothelial
cells [8].
Tumor necrosis factor (TNF)
TNF is a protein known to have a variety of effects on many cells and tissues. Contrary to
what its name implies, TNF can often have promitogenic effects on cells, depending on
conditions which regulate activation of NFkB [6, 15]. TNF is not a direct mitogen for
hepatocytes. The enhance the mitogenic effects of direct mitogens such as HGF, both in vivo and
in cell culture [9] and is mitogenic for hepatocytes with transgenic expression of TGF [10, 18].
TNF increases in plasma after partial resoction. Its cellular source is considered to be the hepatic
macrophages (Kupffer cells) but production by other cell types has not been excluded. TNF
should not be viewed as the initiator of liver regeneration, but rather as one of the many
concurrent and contributory extracellular signals that all together orchestrate the early events of
the response. TNF is also a regulator of iNOS [13], and mice with deficiency in iNOS have
defective liver regeneration [9, 25].
Epidermal Growth Factor (EGF) and Transforming Growth Factor a (TGF-a)
These two factors belong to the EGF family and share a common receptor (EGFR). EGF
is mitogenic for a variety of epithelial cells, hepatocytes, and fibroblasts, and is widely
distributed in tissue secretions and fluids. In healing wounds of the skin, EGF is produced by
keratinocytes, macrophages, and other inflammatory cells that migrate into the area. TGF-a has
homology with EGF, binds to EGFR, and shares most of the biologic activities of EGF. The
EGF receptor is actually a family of four membrane receptors with intrinsic tyrosine kinase
activity [5, 9].
Interleukin 6 (IL-6)
There is abundant literature documenting the crucial role of IL6 in initiation of the acute
phase response in hepatocytes. This is a rapid increase in production by hepatocytes of many
proteins which assist in controlling acute or chronic inflammation [3, 4]. IL6 is produced by
hepatic macrophages. IL6 is not a direct mitogen for hepatocytes and does not enhance the
mitogenic effect of other growth factors. It is, however, a direct mitogen for biliary cells [11, 15]
and it has important effects on integrity of the intrahepatic biliary tree by regulating production
of small proline-rich proteins by cholangiocytes. IL6 does increase in plasma following
hepatectomy. IL6 is probably a factor contributing to optimizing processes of the early stage of
liver regeneration, but it should not be viewed as the initiator of the process [16].
Signaling mechanisms in hepatocyte growth
Molecular studies of gene-expression cascades in the regenerating liver have provided
insights into the signalling pathways that are rapidly activated in the remnant liver post51

hepatectomy. More than 100 immediate-early gees have been identified, which are activated by
normally latent transcription factors at the transition between G0 and G1, before the onset of de
novo protein synthesis. The advent of microarrays expanded this list even further, and gene
expression profiles indicate that some genes show transient up regulation, whereas others
particularly those involved in protein synthesis and cell growth are elevated throughout the
main proliferative response in the regenerating liver [3, 11, 16].
Specific transcription factors, such as nuclear factor NF-B, signal transducer and
activator of transcription STAT3 and AP1, are rapidly activated in remnant hepatocytes minutes
after partial hepatectomy. The intracellular-signalling pathways that involve mitogen-activated
protein kinase (MAPK) and, more specifically, pERKs (phosphorylated extracellular signalregulated kinases), jun amino-terminal kinase (JNK) and receptor tyrosine kinases, are rapidly
activated according to a similar time frame, thereby providing clues to the initiating signals [3, 9,
15].
Genetic and pharmacological approaches have confirmed that regeneration is a complex
process. However, it is now possible to connect many of the proteins that are involved to two
distinct linear pathways that are either cytokine or growth-factor dependent, and to identify
regions of overlap between these two main regulatory mechanisms [2, 25]. Cytokines bind to
their cellular receptors, thereby generating intracellular signals that lead to transcription-factor
activation.
Restoration of liver mass is achieved without the regrowth of the lobes that were resected
at the operation. Instead, growth occurs by enlargement of the lobes that remain after the
operation, a process known as compensatory growth or compensatory hyperplasia. In both
humans and rodents, the end point of liver regeneration after partial hepatectomy is the
restitution of functional mass rather than the reconstitution of the original form [15, 26]
Almost all hepatocytes replicate during liver regeneration after partial hepatectomy.
Because hepatocytes are quiescent cells, it takes them several hours to enter the cell cycle,
progress through G1, and reach the S phase of DNA replication. The wave of hepatocyte
replication is synchronized and is followed by synchronous replication of nonparenchymal cells
(Kupffer cells, endothelial cells, and stellate cells).
There is substantial evidence that hepatocyte proliferation in the regenerating liver is
triggered by the combined actions of cytokines and polypeptide growth factors. With the
exception of the autocrine activity of TGF-a, hepatocyte replication is strictly dependent on
paracrine effects of growth factors and cytokines such as HGF and IL-6 produced by hepatic
nonparenchymal cells. There are two major restriction points for hepatocyte replication: the
G0/G1 transition that bring quiescent hepatocytes into the cell cycle, and the G1/S transition
needed for passage through the late G1 restriction point. Gene expression in the liver
regeneration proceeds in phases, starting with the immediate early gene response, which is a
transient response that corresponds to the G0/G1 transition. More than 100 genes are activated
during this response, including the proto-oncogenes c-FOS and c-JUN, whose products dimerize
to form the transcription factor AP-1. c-MYC, which encodes a transcription factor that activates
many different genes; and other transcription factors, such as NF-kB, STAT-3. The immediate
early gene response sets the stage for the sequential activation of multiple genes, as hepatocytes
progress into the G1 phase. Quiescent hepatocytes become competent to enter the cell cycle
through a priming phase that is mostly mediated by the cytokines TNF and IL-6, and
components of the complement system. Priming signals activate several signal transduction
pathways as a necessary prelude to cell proliferation.
Under the stimulation of HGF, TGFa, and HB-EGF, primed hepatocytes enter the cell
cycle and undergo DNA replication. Norepinephrine, serotonin, insulin, thyroid and growth
hormone, act as adjuvants for liver regeneration, facilitating the entry of hepatocytes into the cell
cycle. Individual hepatocytes replicate once or twice during regeneration and then return to
quiescence in a strictly regulated sequence of events, but the mechanisms of growth cessation
have not been established.
52

Conclusions
Experimentally, hepatocyte proliferation is blocked by the use of the chemical substances
during long-term administration. It was described an increasing number of cells with mixed
biliary and hepatocytic gene expression patterns, as well as some markers of their own [15].
These cells have been called oval cells, from the shape of their nucleus. Oval cells proliferate
intensely in the periportal areas of the hepatic lobule and they are heavily infiltrated by stellate
cells; the latter intertwine with the oval cells and produce HGF, FGF1, FGF2, and VEGF [6, 8, 9,
15]. Oval cells express both albumin and alpha-fetoprotein. The origin of the oval cells has been
much debated. A strong argument for their origin from biliary cells is their early gene expression
patterns which strongly resemble biliary cells, and the fact that biliary cells begin expressing
hepatocyte-associated transcription factors before oval cells appear. There is no histologic
observation demonstrating an oval cell population in any nonbiliary compartment in a normal
liver. Cells equivalent to oval cells, called ductular hepatocytes, are also seen in humans
during fulminant hepatitis following extensive liver injury (by chemicals, viruses, etc.) and they
are assumed to pay a role similar to oval cells in restoring hepatocyte populations.[14, 17]
It should be noted that pancreatic ductules have also been viewed as the source of
progenitor cells for both acinar cells and islet cells of the pancreas [8, 9]. In addition, in vitro
studies have demonstrated the possibility of development of hepatocytes and oval cells from
bone marrow stem cells that are functionally multipotent, capable of self-replication during
symmetric cell division and give rise to progenitor cells during asymmetric cell division, but it
was not properly identified in vivo [9]. The self-renewal is a unique property of stem cells, and
progenitor cells, which are its progenitors, proliferate and differentiate in population of somatic
cells, but are not saved in tissue. They may have one or multilinear potential, but are only able to
short-term of tissues restoration [4, 5].
Despite the fact the adult liver contains undifferentiated stem cells, these cells are not
activated either during the postnatal growth or regeneration after partial hepatectomy [15]. In
these cases, normal growth is due to proliferation of adult hepatocytes. The optional reserve stem
cells of the liver are recruiting only during functional failure when hepatocytes lose the ability to
reproduce.
References
1. Currier, A. R. et al. Plasminogen directs the pleiotropic effects of uPA in liver injury and
repair. Am. J. Physiol. Gastrointest. Liver Physiol. 2003. 284, G508G515.
2. Fausto N. Lessons from genetically engineered animal models. V. Knocking out genes to
study liver regeneration: present and future. Am. J. Physiol. 1999. 277, G917G921.
3. Fey GH, Hattori M, Hocke G, Brechner T, Baffet G, Baumann M, Baumann H,
Northemann W. Gene regulation by interleukin 6. Biochimie 1991;73:4750.
4. Heinrich, P. C. et al. Principles of interleukin (IL)-6-type cytokine signaling and its
regulation. Biochem. J. 2003. 374, 120.
5. Kirillova I, Chaisson M, Fausto N. Tumor necrosis factor induces DNA replication in
hepatic cells through nuclear factor kappaB activation. Cell Growth Differ 1999;10:819
828.
6. Koniaris, L. G., McKillop, I. H., Schwartz, S. I. & Zimmers, T. A. Liver regeneration. J.
Am. Coll. Surg. 2003. 197634659.
7. LeCouter J, Moritz DR, Li B, Phillips GL, Liang XH, Gerber HP, Hillan KJ, Ferrara N.
Angiogenesisin dependent endothelial protection of liver: Role of VEGFR-1. Science
2003; 299:890893.
8. Lindroos PM, Zarnegar R, Michalopoulos GK. Hepatocyte growth factor (hepatopoietin A)
rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by
partial hepatectomy and carbon tetrachloride administration. Hepatology 1991;13:743750.
9. Michalopoulos G. K. Liver Regeneration. *J Cell Physiol. 2007 November ; 213(2): 286
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10. Mars WM, Zarnegar R, Michalopoulos GK. Activation of hepatocyte growth factor by the
plasminogen activators uPA and tPA. Am J Pathol 1993;143:949958.
11. Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J
Biochem 1996;119:591600.
12. Michalopoulos, G. K. & DeFrances, M. C. Liver regeneration. Science. 1997. 276, 6066.
13. Nussler AK, Di Silvio M, Liu ZZ, Geller DA, Freeswick P, Dorko K, Bartoli F, Billiar TR.
Further characterization and comparison of inducible nitric oxide synthase in mouse, rat,
and human hepatocytes. Hepatology 1995;21:15521560.
14. Satyanarayana, A. et al. Telomere shortening impairs organ regeneration by inhibiting cell
cycle re-entry of a subpopulation of cells. EMBO J. 2003. 22, 40034013.
15. Taub R. Liver regeneration 4: Transcriptional control of liver regeneration. Faseb J
1996;10:413427.
16. Taub R. Liver regeneration: From myth to mechanism. Nat Rev Mol Cell Biol 2004;5:836
847.
17. Taub, R., Greenbaum, L. E. & Peng, Y. Transcriptional regulatory signals define cytokinedependent and-independent pathways in liver regeneration. Semin. Liver Dis. 1999. 19,
117127.
18. Wheeler, M. D. et al. Impaired Ras membrane association and activation in PPARa
knockout mice after partial hepatectomy. Am. J. Physiol. Gastrointest. Liver Physiol. 2003.
284, G302G312.
19. . .,
. . 2008, 6, 14-21.

ROLUL PAPILOMAVIRUSURILOR N APARIIA NEOPLAZIILOR EPITELIALE.

Lucian Rudico
Catedra Histologie, Citologie i Embriologie
Summary
Role of papillomaviruses in development epithelial neoplasia
It is demonstrated that papillomaviruses are ethyological factors of crucial importance in
appearance and progression of epithelial neoplastic lesions. In spite of their heterogenity and
polymorphism, these causal agents are able to infect epithelial sites of the species. In case of
humans they may provoke abortive infections, usually with no clinical expression. In case of
concomitant infections papilomaviruses may lead to neoplasia with high risk of malignant
transformation. Papillomaviruses affect exclusively epithelia, using identical mechanisms of
invasion, differences being represented by the ability of the viral genome multiplication that
depends on cellular microenvironment, immune response of the host and proliferative potential
of the infected epithelium.
Rezumat
Este demonstrat ca papilomavirusirile sunt factorii etiologici cruciali n apariia i progresia,
a neoplaziilor epiteliale. n pofida la polimorfismul i heterogenitatea lor, aceti ageni cauzali
sunt capabili s infecteze site-uri epiteliale la una i aceeai specie i dac ne referim la specia
uman, ei pot cauza infecii abortive mai des inaparente i n cazul patologiilor concomitente
pot duce la neoplazii epiteliale cu risc nalt de malignizare. Papilomavirusurile sunt n
exclusivitate epiteliotrope iar mecanismele de invazie sunt identice, diferena fiind reprezentat
de capacitatea virusului de a-i multiplica genomul reieind din specificul celulei gazd,
statutului imun a macroorganismului reactivitatea lui i nu n ultimul rnd de capacitatea de
proliferare a epiteliului.
54

Introducere
Papilomavirusul infecteaz celulele epiteliale i depinde de proliferarea i diferenierea
acestora, pentru asigurarea ciclului su vital. Proteinele virale, sunt prezente iniial n celulele
epiteliele din stratului bazal, i n urma proliferrii se deplaseaz spre suprafaa epiteliului ,
mpreun cu celula gazd. Expresia proteinelor E6, E7(proteine reglarorii codificate de ADN-ul
viral) n celulele stratului bazal al epiteliului, condiioneaz intrarea celulelor infectate n faza-S
a mitozei, n care se realizeaz replicarea genomului viral. Amplificarea genomului viral este
obligatorie, i condiioneaz producerea virionilor infectani. Acest fenomen este unul complex
i depinde de co-expresia mai multor proteine virale care mediaz procesul de sintez.
Componentele proteice structurale ale capsidei virale, sunt evidente n celulele ce conin o alta
protein reglatorie, i anume proteina E4, dar de data aceasta n straturile superioare ale
epiteliului. Sincronizarea acestor evenimente variaz n dependen de tipul virusului
infectant,compatibilitatea lui cu celula gazd i respectiv ne determin s stabilim caracterul i
severitatea neoplaziei or faza productiv a virusurilor depinde dramatic de tipul virusului i
epiteliul infectat n funcie de specie. Nesincroinizarea dintre tip i specie conduce la apariia
infeciilor abortive.
Tipuri de papilomavirusuri umane (HPV)
Papilomavirusurile sunt incluse n mai multe grupuri. Ele pot infecta mai mult de 20 de specii
de psri i reptile. Datorit faptului c HPV reprezint o importan deosebit n aspect medical,
au fost studiate mai mult de o sut tipuri de virusuri cunoscute la moment [5]. Dei clasificarea
papilomavirusurilor a fost stabilit n funcie de nucleotidele omoloage din ADN-ul lor, ntre
diferite grupuri evolutive, este reflectat o similitudine n structura acestora. HPV -ul transmis pe
cale sexual, este inclus n supergrupul A (cunoscut ca Alpha papillomavirus) [17]i virusurile
din acest grup cum ar fi HPV6 i HPV11, provoac patologii sexual transmisibile majore la 1%
din populaia sexual activ. Aceste virusuri pot deasemenea infecta site-uri orale, unde ei sun
asociai n general cu papiloamele benigne. Prin contrast, virusurile din supergrupul A, cum ar fi
HPV16, HPV18 cauzeaz leziuni ale mucoaselor ce pot progresa n neoplazii cu risc nalt de
malignizare i cancer [6]. Dei virusurile din supergrupul A includ tipuri ce au tropism pentru
site-urile cutanate, cum ar fi HPV2 sau HPV10, particularitile comune ale ciclului vital nu se
extind asupra papilomaviruior din aceai grup evolutiv [33]. HPV2 i papilomaviruii
nrudii din supergrupul A, sunt facorii primari ce cauzeaz apariia verucilor.
Grupul scundar major al HPV, este inclus n supergrupul B. Virsurile din subgrupul B1, cum
ar fi HPV5 (Beta papillomavirus) [17] cauzeaz infecii inaparente sau latente n populaia
general, dar poate deveni o problem la indivizii imunosupresai i la cei cu patologii ereditare,
care-i fac susceptibili la infecii cu papilomavirusuri din subgrupul respectiv, i al supergrupului
B. Asfel de pacieni pot dezvolta cancer de piele n urma infeciei cu HPV, i se consider c i
beta papilomavirusul poate fi implicat n dezvoltarea cancerului de piele non-melanomic
(NMSK) n populaia general[29]. Virusurile din subgrupul B2 cum ar fi HPV4 (Gamma
papillomavirus); [17]cauzeaz verucile cutanate n populaia general care pot s se asemene
superficial cu cele cauzate de papilomavirusurile din supergrupul A, cum ar fi HPV2.
Grupul rmas a HPVs- cu risc nalt sunt incluse n supergrupul E. Doar trei virusuri ce
afecteaz specia uman din acest grup sunt cunoscui, i toi cauzeaz papiloma cutanat n
populaia general. HPV1 este cel mai puin studiat virus din acest grup i ca i HPV2 din
supergrupul A cauzeaz veruci i nevi palmari.
Problemele n dezvoltarea modelului general a bolii asociate cu HPV
Din cele expuse mai sus reese c diferite HPV-uri sunt implicate n suplinirea diferitor nie
biologice i c n acela mod virusurile din diferite clase evolutive pot fi abile s inteasca
aceleai site-uri epiteliale. Nectind la heterogenitatea aparent, ntre tiputile de HPV,
caracteristicele lor comune le permit s produca virioni infectani n celulele epiteliale infectate,
indiferent de specie. Toate HPV-urile cunoscute sunt n exclusivitate epiteliotrope, i spre
deosebire de anumite tipuri de papilomavirusuri animale, cum sunt BPV1, BPV2 ele nu
55

infecteaz i nu conin expresia produsului genelor n dermul subiacent. Similar, toate produc
particule infectante n straturile epiteliale superioare dei ele sunt diferite ca i expresie,
depinznd de sinteza virusului, i vor fi transmise prin contact direct (nevi genitali) sau indirect
(veruci)[33]. Cunoscnd la general cum papilomavirusurile privoac boala, devine evident
faptul c fonul volutiv al diferitor virusuri, site-ul lor de infectare i modul lor de transmitere,
necesit ateie dac modelul general urmeaz s fie aplicat n particular, pe anumite tipuri de
HPV. Diferenele n secvenele reglatorii i potenialul de codificare ale genomului viral sunt
destul de clar studiate n biologia diferitor virusuri din acest grup.
Organizarea HPV (ciclul vital)
Un interes deosebit n ultimele decenii a fost acordat studierii, i scoaterii n eviden a
caracteristicilor HPV16, ce este agentul cauzal al cancerului de col uterin.
Iniial virusul necesit acces la celulela stratului bazal , unde poate ajunge prin defectele
epiteliului supraiacelt. Astfel de defecte pot sa nu fie evidente, i pot aparea n condiiile n care
epiteliul este supus microtraumelor.
Pentru ca o leziune s fie meninut, virusul trebuie s infecteze celulele bazale (stem) ale
epiteliului[21]. n epidermul pielii astfel de celule se gasesc din abunden n foliculii pieloi, i
pentru virusurile din supergrupa B1, foliculii pieloi pot fi un important site de infectare sau
poart de intrare. Mai multe studii au artat ca ADN-ul viral din BPV1 poate fi amplificat prin
PCR, n rezultatul prelevrii epiteliului infect din folicolii pieloi [7]. Pentru HPV16 formarea i
meninerea leziunilor cervicale, este facilitat de migrarea celulelor infectate ale epiteliului
stratificat pavimentos n zona de transformare, unde formeaz stratul bazal. Exist receptori la
suparafaa celulei care permit ataarea virusului de membrana celular, dei mai multe studii
denot dependena atarii, de implicarea n acest proces a heparan sulfatului[27]. Este
demonstrat c internalizarea (patrunderea in celul) virionilor ataai, este un proces lent cu
perioada de njumataire de o or, i se produce prin endocitoza virusului prin vezicule ce sunt
consolidate de complexul proteic Clatrin-trickeleon [11].
Decapsidare papilomavirusului este rezultatul scindarii conecsiunilor intracapsometrice a
sapsidei virale, la nivelul membranei celulare, urmnd ca ADN-ul viral s fie transportat n
nucleu.
Meninerea genomului viral
Este demonstrat c dezvoltarea ulterioar a infeciei, se datoreaz meninerii genomului viral
n celul, care este determinat de prezena unui numr stabil de episomi n celulele stratului
bazal al epiteliului pluristratificat scuamos necornificat. Responsabile de meninerea ADN-lui
viral ca i episomi n respecrivele celule, se fac proteinele virale reglatorii E1 i E2 care
faciliteaz segregrea corect a genomului pe parcursul diviziunii celulei gazd. Insuficiena
expresiei genei ce codific pentru E1, nu permite meninerea episomilor[24]. Se presupune c
genomul viral este pastrat n celulele stratului bazal al epiteliului, ntr-un numar de aproximativ
10-200 de copii per celula, i c aceste proteine precoce (E6, E7,E1i E2) sunt exprimate n
straturile celulare inferioare ale epiteliului[16]. Aportul proteinelor E6 i E7 n proliferarea
celulelor bazale, n cadrul infeciei in vivo, la moment este incert, dar este cert faptul c prezena
proteinelor reglatorii E1 i E2, sunt suficiente pentru meninerea episomilor virali n celulele
stratului bazal al epiteliului.
Faza proliferariv
n epiteliul neinfectat, celulele bazale divizndu-se se deplaseaz in stratul suprabazal, unde
sunt supuse transformarii terminale. Schimbarile includ transformarea fizica a filamentelor
intermediare constituite din cheratina, cu formarea anvelopei epiteliale cornificate, i secreia
lipidelor, care impreuna formeaza o bariera fizica, ce protejeaza de aciunea factorilor mediului
extern.
n infecia cu papilomavirus, E7 i deasemenea E6 se exprim n aceste celule, astfel nct
ciclul celular este ncetinit, iar diferemierea terminal a celulelor epiteliale stagnat. Se
consider c E6 i E7 i desfaoar aciunea concomitent pentru a realiza aceste efecte (inclusiv
i n leziunile cauzate de infecia HPV cu risc inalt precum HPV16), ele fiind doua proteine ce
56

sunt codificate de ARNm bicistronic de la promotorul viral precoce (p97). E6 i E7 stimuleaz

progresul ciclului celular, i ambele pot asocia cu reglatorii ciclului celular. Asocierea E7 cu
proteinele din grupul pRb este bine cunoscut. pRb este un reglator negativ a cilului celular care
n mod normal previne intrarea celulei n faza-S a interfazei, dupa asocierea cu factorii de
transcripie proteinele grupului E2F. Conexiunea E7 - pRb disocoaz grupul E2F indiferent de
aciunea factorilor de cretere externi, asfel exprimndu-se proteinele necesare procesului de
replicare a ADN-lui. E7 se poate asocia deasemena i cu alte proteine implicate n procesul de
proliferare celular cum ar fi diacetilazele histonice, componente ale complexului de transcripie
AP-1[1], i inhibitorii chinazici ciclin-dependeni p21 i p27 [25]. Necatnd c abilitatea E7 de a
stimula proliferarea celular este destul de marcat, n timpul infeciei productive doar o
subdiviziune celular este mitotic activ n straturile parabazale.
Expresia cilinei E, este absolut necesar penru intrarea celulelor in faza-S a interfazei i se
manifest n timpul infeciei, ca rezultat al exprimarii E7 i a distrugerii complexului E2F/pRb.
n procesul de difereniere a celulelor epiteliale, oricum, n straturile superficiale ale epiteiului,
inhibitorii chinazici ciclin- dependeni (p21cip1 i p27kip1) pot duce la formarea de complexe
inactive, ce conin E7, ciclina E/cdk2, i nicidecum p21sau p27. Se pare c , n timpul infeciei
naturale, abilitatea E7 de a stimula intrarea in faza-S este limitata la grupul celulelor difereniate
care conin nivele scazute de p21/p27, sau care expima nivele insuficiente de E7, necesare pentru
a debloca procesul de intrare n faza-S.
Proteina viral E6 complementeaz rolul E7 i se consider ca previne inducerea apoptozei ca
rspuns la intrzierea procesului de intrare n faza-S mediat de E7. Dei asocierea E6 cu p53 i
inactivarea supresiei mrite p53 mediate i/sau apoptoza, a fost bine documentat, E6 se poate
deasemenea asocia cu alte proteine pro-apoptotice cum ar fi Bak i Bax. Ca i consecin,
prezena de E6 este considerat un factor predispozant n apariia cancerelor asociate cu infecia
HPV, permind acumularea erorilor n ADN, ca urmare a omiterii punctelor de restricie, i
controlul calitii informaiei genetice. Proteina E6 n infecii HPV cu risc nalt, pot deasemenea
simula proliferarea celulei independent de E7 prin domeniul sau PDZ-ligand al terminalului-C.
Conexiunea E6-PDZ este suficient pentru a media proliferarea celulelor suprabazale, i poate
contribui la diseminarea metastatic ca urmare a dispariiei jonciunilor intercelulare normale. De
rind cu E6 i E7, este demonstrat existena proteinelor virale precoce (E1,E2,E4 i E5)
expresive anterior invaziei i replicarii genomului, responsabile de meninerea episomilor virali
intr-un numar mic de copii [33].
Amplificarea genomului viral
Pentru producerea virionilor infectani, papilomavirusurile trebuie s-i amplifice genomii si
virali, i s-i npacheteze n particule infecioase. Pentru supergrupul A, tipurile de HPV cum ar
fi, HPV16 ,HPV11 sau HPV2, este specific desfaurarea acestor procese n straturile
intermediare sau superficiale ale epiteliului, ca urmare a creterii activitaii promotorilor tardivi
(dependeni de diferenciere). Promotorul tardiv este gena ce codific proteina E7. Respecriva
gen este accesibil transcripiei i este situat in segmentul reglator a ADN-ului viral, E7
reprezentnd structura proteica responsabil de reglarea proliferarii celulare prin asigurarea
intrarii lor in faza-S. Amplificarea genomilor virali ncepe n stratul bazal proliferativ i
presupune creterea expresivitaii tuturor proteinelor codificate de promotorii virali precoce cum
ar fi E4 i E5[22], ale cror roluri n replicare, sunt mai puin nelese.
Conexiunea E2 cu regiunea reglatorie a genomului HPV, este necesar pentru replicare ADNlui viral, iar la originea viral a replicrii se afl helicaza ADN-ului E1. Asamblarea comlexului
de iniiere E1/E2 de origine viral este similar cu formarea comlexului ntre proteinele de
iniiere a replicrii celulare (cdc6 i MCMs), i poate induce replicarea genomilor virali, n
absena sintezei ADN-ului celulei gazd. Pe parcursul ciclului vital al virusului, nivelele relative
a diferitor proteine virale sunt controlate de utilizarea promotorilor i de selecia diferenial a
mbinrii de poziii. Odat cu creterea expresiei de E1 i E2 la acest nivel, urmeaz creterea
numarului de copii virale n straturile epiteliale superficiale. Mecanismele moleculare care
conduc la activarea promotorului tardiv i reglarea expresiei E1/E2, nu sunt nc bine elucidate,
57

i aceasta din cauza c promotorul tardiv este activ pe tot parcursul ciclului viral productiv.
Modelele recente sugereaz c la o cretere modest a activitaii promotorilor tardivi pe
parcursul diferenierii celulare, poate duce i la creterea expresiei E1 i E2 (deasemenea E4 i
E5), i ca i consecin - creterea numarului de copii ale genomului viral. Noul material genetic,
primit n urma replicrilor, servete drept machet pentru ulterioara expresie a E1 i E2,
facilitnd la rindul su, amlificarea adiional a genomilor virali [33].
Sinteza virusului
Papilomavirusurile codifica dou proteine structurale, care se exprima n straturile superioare
a esutului infectat, ce se produce conconitent cu finisarea procesului de amplificare a
genomului. L2 reprezit o protein structural minor care ca i L1 este produs de subgrupul de
celule care exprima E4 [19][20]. Proteina capsidic majora L1, este evideniat dup expresia
L2, ceea ce denot asamblarea particulelor infecioase n straturile superioare ale epiteliului [23].
Particulele papilomavirusului conin aproximativ 8000 de perechi de baze in genom, pe cnd o
capsida conine 360 de copii a proteinei L1 i 12 copii de L2, organizate in 72 de capsomere.
Proteina L2 acumuleaza structuri globulare cunoscute ca i corpusculuii PML pe parcursul
asamblrii virusului (posibil prin asocierea cu transcrierea factorului Dax) asamblind proteina
majora L1 n domenii. Se presupune c corpusculii PML pot fi site-uri de replicare a ADN-ului
papilomaviruilior [15] i aceste proteine capsidice se acumuleaz pe aceste site-uri, facilitind
mpachetarea. Dei pariculele virale por fi asamblate n absena L2, proteina L2 sporete
mpachetarea virionilor i virulena lor. Din acest moment virusul trebuie s evadeze eventual
din celula epitelial infectat, i s supraveuiasca extracelular, nainte de reinfectare.
Papilomavirusurile nu sunt litice, i nu sunt eliberate pn cnd celulele infectate nu ajung la
suprafaa epiteliului [9][10]. Odat cu deplasarea celulelor spre straturile superficiale ele
epiteliului, o eventuala retenie n aceste celule a atigenilor papilovavirusurilor, pot compromite
detectarea imun a virusului, datorit faptului c virusul de obicei posed mecanisme moleculare
care limiteaz prezentarea epitopilor virali, celulelor imunocompetente, ncepnd din straturile
inferioare ale epiteliului[3]. Dei expresia proteinelor virale pot inhiba expresia diferenierii
marcherilor, prevenind cornificarea scuamoas obinuit [19][20], este bine cunoscut faptul c
proteina viral E4, poate contribui direct la ieirea virusului din celulele straturilor epiteliale
superficiale, dup perturbarea asamblrii cheratinei [19][20] i afectarea organizrii inveliului
scuamos cornificat [9][10].
Organizarea ciclului vital la diferite tipuri de HPV
Dei toate papilomavirusurile trebuie s urmeze cascada evenimentelor descrise mai sus, n
ordinea producerii virionilor infectani, diferite strategii a infeciei productive sunt aparente ntre
diferite grupuri evolutive. Papilomavirusurile umane din supergrupul B2, precum HPV4, nu
conin site-ul LXCXE necesar pentru asocierea cu pRb i proteina comun E7, presupunind c
la nivel molecular ele pot opera diferit n comparaie cu papilomavirusurile supergrupului A,
cum ar fi HPV2, care cauzeaz leziuni n locuri similare. n acela mod, proteina E4 a HPV4
previne polimerizarea monomerilor keratinei, n celulele epiteliale din sraturile superficiale, de
rnd cu aceeai protein produs de HPV1(supergrupul E) i HPV2 (supergrupul A) [19][20],
favorizind ieirea virusului din celulele epiteliale scuamoase cornificate. Analizele comparative a
papilomavirusurilor de diferite tipuri, au demonstrat c segmantele de ADN viral ce codific E1
i L1 sunt cele mai conservate[17]. Se pare ca aceste gene sunt fundamentale i indispensabile
pentru supraveuirea papilomavirusurilor. Nectnd la diversitatea papilomavirusurilor, se pare c
virusurile din grupele evoluive relatate, dispun de anumite similaritai. Acestea pot fi ilustrate
dup compararea papilomavirusurilor coninui n supergrupul E (cum ar fi HPV1) care
mpreuna cu cei din supergrupul A (HPV2), provoac apariia verucilor. n primul grup care
include papilomavirusul oral canin (COPV), amplificarea genomului ncepe cu att mai devreme
cu ct celulele parasesc stratul bazal, fr intervenirea caracteristic a fazei proliferative a
virusurilor aa precum HPV2 sau HPV11[33]. S-a speculat ca aceste divergene pot argumenta
existena cilor diferite de transmitere a diferitor tipuri de HPV, i necesitatea de a produce un
numar suficient de particule virale care s permit infectarea far stimularea sistemului imun.
58

Este la fel de posibil ca simbioza dintre papilomavirusuri i gazde s fi condus la adoptarea de

diferite strategii generale n evoluia virusurilor, pentru ca pin la urm, s fie atins acela scop.
Regresia leziunilor i latena virusului
Dei amplificarea genomului i mpachetarea sunt necesare pentru formarea noilor virioni,
infecia poate avea alte consecine. Inocularea experimental ROPV iepurilor, sau inocularea
COPV cinilor, n general duc la dezvoltarea leziunilor care pot persista cteva saptamni i nu
neaparat ani[11]. Leziunile produse de ROPV i COPV se aseaman cu cele produse de HVPuri, i aceti virusuri s-au propus ca modele pentru a studia infecia HPV a mucoaselor la specia
uman. ntre sptaminile 8-12 de la infectare, are loc infiltrarea cu limfocite a epiteliului i
regresia leziunii, iar la saptamina a 16 spaiul infectat are aspectul unui epiteliu sanatos .
Importana sistemului imun n controlul duratei bolii asociate cu HPV, este bine stabilit la
pacianii cu imunodeficien, care sunt susceptibili la infecii i pot dezvolta leziuni pe scar
larg, refractare la tratament. Infeciile cu HPV sunt o problem particular n transplantologia
renal i a pacienilor imunosupresai , HIV pozitivi i pacienii cu defecte genetice, ce au
repercusiune asupra celulelor imune. Infeciile inaparente asociate cu virusurile din supergrupul
B1 se pot asemna cu infeciile altor tiputi de HPV dar care au fost supuse controlului de ctre
sistemul imun al gazdei. Detectarea frecvent de HPV16 n leziunile cervicale, n lipsa leziunilor
evidente poate fi explicat prin prezena virusului n stare latent, cu doar foarte puine celule n
faza productiv pe fonul diferenierii celulelor epiteliale. Ca urmare a regresiei leziunilor, sub
aciunea sistemului imun, ADN-ul papilomavirusurilor se consider ca rmine n celulele
epiteliale bazale, i poare fi reactivat la dereglarea homeostaziei imune. Paternul expresiei genei
virale din stratul bazal, n cadrul infeciei latente, poate fi similar paternului expresiei genei din
aceste straturi, n faza productiv. Se consider c expresia genelor n faza latent, este limitat
la E1 i E2, pe cnd E6 i E7 , n cadrul aceleai infecii, nu sunt exprimate.
Infecia productiv, infecia abortiv i cancerele asociate cu HPV
n absena regresiei, leziunile pot persista i n anumite condiii pot progresa pna la cancer. O
caracteristic comun a virusurilor tumorale este abilitatea lor de a cauza tumori n locurile unde
ciclul lor vital nu este complet. Aceast caracteristic general pare s conin adevrul desptre
cancerele asociate cu papilomavirusul, aa precum cele cauzate de CRPV la iepurii domestici, i
BPV1 la cai. HPV-urile cu risc nalt din supergrupul A, au fost asociate cu cancerele cervicale la
femei, ntruct virusurile din supergrupul B n particular B1, sunt implicai n dezvoltarea
cancerului de piele non-melanomic [29]. Dac e s comparm prevalena infeciilor cu HPV n
populaia general numrul leziunilor ce progreseaz spre cancer este foarte mic.
Papilomavirusurile cu risc nalt din supergrupul A, infecteaz zonele genitale la barbai i la
femei, i cauzeaz leziuni plate, la nivelul cervixului uterin. La femeile care nu s-au tratat, aa
leziuni pot progresa spre neoplazie intraepitelial cervicala gr.1 (CIN1) CIN2, CIN 3 i
cancer[28]. Leziunile cervicale cu grad scazut, CIN1, se aseaman cu infeciile productive,
cauzate de tipurile relatate de HPV, n leziunile cu grad nalt, aa precum CIN2, CIN3, este o
faz proliferativ mai extins, de durat, cu stadii productive ale ciclului vital al virusului [33].
Cheia evenimentelor n progresia, leziunilor productive cu grad nalt, spre neoplazie, poate
rezulta pe deoparte din dereglarea expresiei proteinelor de transformare viral E6 i E7, care duc
la proliferarea celular marcat, n straturile inferioare ale epiteliului, i pe dealt parte din
incapacitatea de a repara mutaiile secundare n ADN-ul celulei gazd. n general se consider c
zona de tranziie este un loc particular care permite dezvoltarea cancerului cervical. Este
cunoscut faptul c tipurile de HPV cu risc nalt aa ca HPV16, nu-i pot asigura complet ciclul
lor vital n aceasta zon, ocazional ducnd la infecii abortive. Progresul de la CIN3 la cancer, de
obicei se datoreaz prezenei leziunilor ce conin copii integrale ale genomului viral, n care
expresia E7 este crescut. Ca urmare, retenia genelor E6 i E7, concomitent cu pierderea genelor
E2 i E4, ce pot exercita efecte negative asupra celulei n cretere, deobicei acompaniaz
dezvoltarea cancerului cervical invaziv. Dei alte tipuri de HPV, aa ca cele din supergrupul B1
sunt adesea asociate cu cancerele umane (cancerul de piele non-melanomic), n aceste cazuri
succesiunea proceselor de integrare a HPV n genomul celulei gazd nu sunt necesare[29, 30].
59

Organizarea ciclului vital ale papilomaviruilor la animale

Conceptele generale relateaz c ciclurile vitale ale papilomaviruilor umani apar pentru a fi
aplicabili pe sistemele animale, ulterior utilizate n cadrul studierii infeciilor. n majoritatea
cazurilor papilomavirusurile animale sunt incluse n grupuri, n care nu se conin
papilomavirusuri umane, ceea ce denot faptul c ei au urmat o cale evolutiv care este diferit
de cea a HPV-urilor[16]. Fac excepie virusurile din supergrupul B, care sunt rspndii la
animale[2], dei virusurile din supergrupul E, au fost detectae la iepuri pisici i cini. Din punct
de vedere al medicinei, cele mai importante virusuri din supergrupul E, apar doar la primate. Cu
excepia papilomavirusurilor rspndite la bovine (BPV), celelalte virusuri nu au fost prea mult
studiae la animale. BPV1 i BPV2 sunt fibropapilomavirusuri ce produc leziuni care au
fundamentat implicarea dermal. BPV1 cauzeaz nevi cutanai n gazda sa natural, dar induce
tumorile fibroblastice la cai. Cu toate c acete virusuri au fost foarte bine studiae, din cauza
abilitii lor de a transforma celulele n culturile celulare, ele sunt din punct de vedere evolutiv
mai deosebite de papilomavirusurile care cauzeaz tumori la oameni. Al doilea grup important
de papilomavirusuri animali includ BPV4, care pot iduce tumori gasro-intestinale. Ca i alte
papilomavirusuri ce induc cancerul, se tie c infecia duce la expansiunea celular, i asta n
prezena co-cancerigenilor, acumularea erorilor genetice, ce deasemenea duc la malignizare.
Respectiv, studiul amnunit asupra impactului etiologic al virusurilor n neoplaziile
epiteliale, mecanismele moleculare ce duc la apariia celulelor maligne, este o direcie prioritar
i absolut necesar n vederea stabilirii unor noi viziuni i principii de tratament, cu perspective
feroce n oncologia modern.
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ANATOMIA CLINIC A SPLINEI

Olga Belic
Catedra Anatomia Omului, USMF ,,Nicolae Testemianu
Summary
Spleen clinical anatomy
It has been established that the spleen is innervated by lineal, pancreatic plexuses of nerves
and vascularised trough lienal arteries, using the macroscopic method. The lienal artery passes
along the superior margin of the pancreas in 54, 4% of cases, in 12, 3% of cases it passes above
the pancreas. In 11, 1% of cases the artery was located behind the posterior margin of the
pancreas, and in 2, 5% of cases it was located on the anterior surface of the pancreatic body. In
19, 7 % of cases the artery was located within the parenchyma of the pancreas. It has been
established by means of macroscopic and statistical methods that an accessory spleen is most
commonly detected near the lineal hilus of the basic organ, it is supplied by the branches of the
lienal artery and innervated by the nerve trunks of the lienal and pancreatic plexuses.
Rezumat
Prin metoda de disecie macroscopic s-a stabilit c splina este inervat de ctre nervii
plexurilor lienal, pancreatic i vascularizat prin ramurile arterei lienale. Artera lienal este
amplasat pe marginea superioar a pancreasului n 44(54,4%) cazuri, mai sus de pancreas n
10 (12,3%) cazuri. Posterior marjinii superioare a pancreasului, vasul a fost ntlnit n 9(11,1%)
cazuri i pe faa anterioar a corpului pancreatic n 2(2,5%) cazuri. n parenchimul glandei
artera a fost situat n 16(19,7%) cazuri. Metodele macroscopic i statistice arat c splina
accesorie este localizat mai frecvent n regiunea hilului lienal, se vascularizeaz prin ramurile
arterei lienale i este la fel, inervat de ctre nervii plexurilor lienal i pancreatic.
Actualitatea
Splina este un organ parenchimatos impar de consisten friabil cu importante funcii
imunologice i hematologice. Cunoaterea varietii formelor, dimensiunilor organului,
aspectelor structurale i topografice ale vaselor sangvine ale splinei, relaii cu organele adiacente
trebuie luate n consideraie n timpul interveniilor chirurgicale planificate i urgente, pe
organele imunocompetente, ndeosebi acum n legtur cu lrgirea cercului de intervenii
chirurgicale, cu includerea principiilor de pstrare maxim a organelor lezate prin traumatisme
asociate sau izolate ale abdomenului. Splenorafia, deseori, este considerat periculoas din cauza
riscului de sngerare din esuturile splinei suturate. Acest pericol poate fi redus prin
mbuntirea tehnicii chirurgicale i prin cunoaterea detaliat a anatomiei sistemului vascular al
organului vizat [11].

62

Material i metode
Anatomia variabilitii individuale, n funcie de vrst i sex, a plexului lienal, precum i a
splinei a fost studiat prin metoda de disecie macroscopic fin, propus de . . i
. . .
Pentru stabilirea frecvenei splinei accesorii n aspect clinic, au fost analizate 257 de
tomograme n Centrul Naional tiinifico-Practic n Domeniul Medicinii de Urgen. Rezultatele
au fost analizate prin metode statistice, n funcie de particularitile de vrst i sexul
pacienilor, i prelucrate cu ajutorul programei Excel. Au fost calculai parametrii de rspndire a
structurii i raportul lor, iar veridicitatea rezultatelor a fost bazat pe calcularea criteriului tstudent par. Sistemul vascular al splinei a fost examinat prin analiza a 106 de panaortograme.
Rezultate i discuii
Splina este situat n hipocondrul stng al cavitii abdominale, la nivelul coastelor IX
XI, n loja splenic cuprins ntre diafragm, stomac, coada pancreasului, unghiul stng al
colonului i rinichiul stng. La splin distingem: faa diafragmatic, convex orientat spre
diafragm; faa visceral, concav, neregulat ce comport hilul lienal prin care ptrunde artera
lienal, nervi i ies vena lienal. Organul are o lungime de 12 14 cm, lime de 8 cm, grosime
de 4 cm. Volumul i masa splinei variaz n dependen de activitatea hematopoietic i de
cantitatea de snge depozitat.
Dimensiunile splinei au fost studiate la adolesceni i maturi (tab. 1, 2), i n dependena de
sex (tab. 3, 4).
Tabelul 1. Dimensiunile splinei la maturi
Din literatura
M0 ES0 mm
132,3 8,06
86,3 4,72

Lungimea
Limea

Studiul propriu
M1 ES1 mm
106,2 2,32
45,8 1,62

3,11
8,11

< 0,01
< 0,001

Tabelul 2. Dimensiunile splinei n adolescen

Din literatura
M0 ES0 mm
74,5 2,16
46,5 0,72

Lungimea
Limea

Studiul propriu
M1 ES1 mm
85,5 1,37
46,8 0,85

4,29
0,27

< 0,001
> 0,05

Comparnd rezultatele obinute despre dimensiunile splinei cu datele din literatura de

specialitate, putem afirma c exist diferen statistic semnificativ n limea la maturi i n
lungime n perioada juvenil (p < 0,001).
Tabelul 3. Lungimea splinei n funcie de sex (mm)
Grupele*
de vrst
VII gr
VIII1 gr.
VIII2 gr.
IX gr.
X gr.
Total

Brbai
Abs.
5
8
32
10
55

Femei

X1 ES1 mm Abs.
85,3 0,7
9
102,7 0,4
17
106,6 0,3
5
114,8 0,08
21
9
102,3 0,2
101
63

X2 ES2 mm
85,7 0,03
108,2 0,6
4 107,4 0,2

0,57
7,64
13,06

100,0 0,3
106,8 0,2
101,6 0,3

47,74
534,0
1,94

p
>0,05
<0,001
<0,001
<0,001
<0,001
>0,05

Tabelul 4. Limea splinei n funcie de sex (mm)

Brbai

Femei

Grupele
de vrst
t
p
Abs.
X1 ES1 mm Abs.
X2 ES2 mm
VII gr.
5
47,7 0,9
9
46,0 0,8
1,42
>0,05
VIII1 gr.
8
46,5 0,8
17
44,5 0,7
1,82
>0,05
VIII2 gr.
32
46,7 0,8
45
45,8 0,6
0,9
>0,05
IX gr.
10
57,1 0,6
21
43,8 0,5
17,05
<0,001
X gr.
9
43,5 0,9
48,3
<0,001
Total
55
49,5 0,7
101
44,7 0,7
4,85
<0,001
*
Not : Repartizarea materialului investigat conform perioadelor ontogenezei are la baz
periodizarea de vrst adoptat la Simpozionul Institutului de fiziologie de vrst a AP URSS
(dup . . (1969), . . , . . (1991), precum i cea propus
de R. Robacki (citat dup M. tefane et al., 2000). Femei : VII 16-20 ani, VIII1 21-35 ani,
VIII2 - 36-55 ani, IX 56-74 ani, X 75-90 ani. Brbai: VII 17-21 ani, VIII1 22-35 ani,
VIII2 -36-60 ani, IX 61-74 ani.
Conform datelor obinute lungimea organului n funcie de sex nu are diferena
semnificativ n total. Diferena exist n grupa IX perioada presenil (56-74 ani femei i 6174 ani brbai) (tab.3). Limea splinei n funcie de sex are n total diferena semnificativ (t =
4, 85) i n grupa IX de vrst 17, 05 (tab. 4).
Nu exist opinie unic despre forma splinei. Rezultatele cercetrilor permit a considera c
forma splinei este supus unor modificri individuale, ce reprezint reflectarea unor pronunate
varieti n forma organului n procesul ontogenezii. Diversitatea formelor splinei poate fi
explicat prin dezvoltarea necoerent a organului i prin influena dimensiunilor, formei
organelor vecine.
A fost studiat forma splinei n diferite perioade a ontogenezei. Conform cercetrile
noastre, formele principale ale splinei sunt: alungit, rotund i intermediar. Au fost stabilite
diferenele semnificative statistice (p < 0, 05) dintre forma splinei alungit i intermediar la
brbai i femei (tab. 5). Nu a fost depistat nici un caz cu forma splinei rotund.
Tabelul 5. Frecvena tipurilor formei splinei n funcie de sex

< 63 %
alungit
63,0 - 75,0%
intermediar
76,0% >
rotund

Abs.
26
29
-

Brbai, n = 55
P ES%
47,3 5,35

Abs.
220

52,7 4,28

112

Femei, n = 32
P ES%
62,5 5,19

22,03

<0,05

37,5 4,02

22,58

<0,05

--

Not*: Tipurile formei organului erau studiate cu ajutorul indexului splinei:

IS=
*100%. Cnd IS este mai mic de 63% forma splinei este alungit, de la
63, 0 75, 0%
intermediar, iar dac IS este mai mare de 76, 0% forma rotund (. .
, 1985).
Trebuie de menionat, c la brbai forma splinei alungit s-a depistat n grupele de vrst
VII, VIII1 i IX (5 4, 02%).
La brbai mai frecvent 47, 3 5, 35 % de cazuri), iar la femei IX i X (62, 5 5, 19%
de cazuri).
64

Forma splinei intermediar a fost la brbai n grupele de vrst VIII2 i X (52, 7 4,

28%), iar la femei VIII2 (37, se ntlnete forma splinei intermediar de 1, 1 ori, dect la Splina
este acoperit de o capsul fibroas, care concrete spre exterior cu peritoneul visceral. Ea este
constituit din esut conjunctiv cu multe fibre musculare netede. Grosimea capsulei variaz de la
un sector al splinei la altul, ns este mai pronunat n regiunea hilului, prin care trec vasele
sanguine i limfatice de la capsul n interiorul organului pornesc trabecule splenice, ce
anastomozeaz ntre ele.
Structura tunicilor conjunctive (seroas i fibroas) ale splinei prezint unele
particulariti morfofuncionale care asigur, pe de o parte, tenacitatea lor, iar pe de alt parte,
ofer organului posibilitile la extensie.
Capsula splinei este format din esut conjunctiv i are structura n straturi. [4], descriu n
structura capsulei reea dens de esut conjunctiv, din care ies trabeculi care impart parenchimul
n nite compartimente incomplete.
Dup [16] splina este incapsulat n tunica musculofibrilar. n regiunea hilului capsula
se ramific n trabecule care insoesc nervii i arterele n interiorul pulpei splinei. esutul
conjunctiv al capsulei i trabeculelor conine doar un numr mic de celule musculare netede.
Trabeculele conin mai multe elemente contractile dect capsula. Ele strbat organul
reprezentnd nu numai structuri de ataare a citoreticulului ci i cile de trecere ale vaselor
sanguine. Conform [7], colagenul fibrilar de tip III contribuie la structurarea trabeculelor
splenice care nsoesc vasele intrasplenice, avnd o dispoziie perivascular i ndeosebi
periarterial, lund denumirea de capsula perivascular intrasplenic.
Peritoneul visceral tapeteaz splina, concrete intim cu tunica ei fibroz i asigur
organului funcia mecanic i participarea n barier hematolimfoseroas. n peritoneu se
mpletesc ligamentele splinei (gastrolienal, frenicolienal, pancreaticosplenic, splenorenal) care
posed o serie de funcii importante pentru organ.
Aparatul ligamentar al splinei constituie un sistem integral care determin topografia,
particularitile inervaiei, vascularizaiei, corelaiile i independena funcional a organului.
Ligamentele splinei ndeplinesc rol de amortizor biologic i calea de acces a surselor de
vascularizare i inervare a splinei.
Ligamentul gastrolienal prezint o duplicatur a peritoneului. ntre 2 foie ale
ligamentului se afl o cantitate mic de esut adipos, prin care trec vase limfatice, arterele i
venele gastrice scurte i gasroepiploice stngi.
Rolul principal n fixarea splinei i se atribuie ligamentului frenicolienal. n componena
ligamentului deosebim dou foie ale peritoneului, care ncep pe partea lombar a diafragmului.
Ligamentul, cu foia sa dorsal, se prelungete n jos, acoper o parte din rinichiul stng formnd
ligamentul splenicorenal. Poriunea inferioar a foiei anterioare se ntinde de la coada
pancreasului pn la hilul splinei i se numete ligamentul pancreaticolienal.
n mobilizarea splinei este necesar de a ine cont de unele particulariti anatomice ale
aparatului ligamentar, care determin alegerea proceselor tehnice [11].
n inervaia splinei particip nervii plexurilor celiac, lienal, ramurile nervului vag.
Plexul celiac este situat pe ambele pri ale trunchiului celiac, n adncul mezogastrului i
se ntinde lateral pn la glandele suprarenale. Direcia ramurilor nervoase ale plexului variaz
foarte larg faptul ce duce la formarea sectoarelor cu suprapunere, inervaie dubl sau a unei
reele de nervi, bogate n jonciuni, amplasate n mai multe straturi. Forma acestui conglomerat
masiv este individual n fiecare caz aparte. De la plexul celiac pleac un numr mare de ramuri,
care nsoesc artera lienal i formeaz plexul lienal. Nervii plexului lienal au o direcie paralel
cu traiectul vaselor, formnd pe peretele lor anse alungite. Studierea arhitectonicii plexului i a
relaiilor lui cu artera lienal n diferite poriuni ale vasului (n sectorul proximal, n partea
medie) a artat, c nervii nconjoar artera din toate prile.
La aduli, n jurul arterei lienale exist o mpletire dens a fibrelor nervoase de calibru
mare, cu formarea unor anse mari, alungite pe parcursul vasului i care cuprind artera n form
de manon.
65

Sunt diferite forme de distribuire a nervilor: trunchuleele nervoase merg mpreun cu

artera i vena, nfurnd pereii lor ntr-o msur egal aceasta are loc n cazul cnd vasele
merg paralel i sunt situate foarte aproape unul de cellalt. n acest caz un numr mare de
trunchiulee nervoase este situat pe partea anterioar sau posterioar a vasului. Este necesar de
subliniat, c pe parcursul arterei nervii trec de pe o suprafa a vasului pe alta, schimbnd metoda
de conectare a trunchiuleelor nervoase. A treia form a plexului lienal este cnd trunchiuleele
nervoase de baz merg mult mai jos de parcursul vasului arterial, trimind ctre arter i ven
rmurele subiri. Aceast form se ntlnete n cazul, cnd vasele se gsesc la o distan
considerabil sau n cazul, cnd artera lienal are un traiect sinuos pronunat, situndu-se de
asupra pancreasului, iar vasul venos are un parcurs rectiliniu i merge prin parenchimul glandei,
aproape de marginea ei superioar. Structura plexului lienal nu este uniform peste tot. n partea
proximal plexul lienal este alctuit din fibre nervoase groase, care se detaeaz greu de peretele
vascular al arterei. Pe parcursul arterei lienale toat reeaua nervoas perivascular se mpletete
n nenumrate rnduri, se rarefiaz. n partea medie cantitatea rmurelelor se micoreaz, fibrele
nervoase devin mai subiri.
n regiunea hilului lienal plexul este structurat n dou forme marginale. n cazul unei
forme concentrate la o oarecare distan de la hilul lienal plexul nervos se divizeaz n dou
fascicule. Jumtatea superioar a splinei se inerveaz de fascicolul superior al plexului, iar cea
inferioar din contul fasciculului inferior. Mai des fascicolul superior inerveaz 2/3 superioare
a parenchimului organului, iar restul splinei este inervat de fascicolul inferior destul de
pronunat.
Mai rar n poriunea inferioar a splinei (2/3) are loc ramificarea fascicolului inferior, iar
n treimea superioar a organului fascicolului superior. La aceast form legturi ntre plexul
lienal i alte plexuri sunt mai puine.
De la plexul lienal ctre plexurile anterior i posterior ale pancreasului pornesc ramuri
relativ subiri, care ptrund n esutul glandei pe traiectul vaselor arteriale i venoase sau de
sinestttor. Att n locul conexiunii trunchiurilor nervoase, ct i pe parcursul ramurilor
nervoase pot fi ngrori de diferite dimensiuni ganglioni nervoi.
La inervaia splinei particip i nervul vag. Fascicule nervoase directe de la trunchiul
posterior al nervului vag trec pe faa posterioar a ligamentului gastrolienal i intr n
profunzimea ligamentelor splinorenal i pancreatolienal. Pe traectul su nervii se unesc cu
ramurile plexului celiac, sau merg mpreun cu ramurile lui, formnd sectoare de inervaie dubl,
de suprapunere, care pot fi tratate drept component compensator. n componena ligamentelor
splinorenal i pancreatolienal fasciculele nervoase ajung la capsula splinei continundu-i calea
n parenchimul organului.
Cunoaterea aspectelor structurale i topografice a vaselor sangvine ale splinei este
important n cazul interveniilor operatorii. Analiza pieselor anatomice (81 de complexe) au
permis stabilirea faptului c principala surs de vascularizaie a splinei este artera lienal,
a.lienalis, cu originea de la trunchiul celiac printr-un trunchi unic.
Dimensiunile liniare ale arterei lienale variaz mult n funcie de perioada de vrst,
apartenena de sex, constituia corporal i particularitile individuale ale persoanelor de la care
se preleveaz materialul de studiu. Astfel, diametrul segmentului incipient al arterei lienale
oscileaz ntre 4 i 11 mm; el se reduce pe msura apropierii de hilul splenic. Lungimea medie a
arterei lienale constituie 9 14 cm. Potrivit relatrii lui [15], lungimea medie att a arterei
lienale, ct i a venei omonime, la maturi, nu se modific. Acest parametru capt valori diferite,
statistic veridice, la persoane trecute de 60 de ani, atingnd maximumul posibil la persoane de
vrst senil.
Este bine cunoscut faptul c distana de la originea arterei lienale pn la splin este mai
scurt n raport cu lungimea aceluiai vas. Aceasta se datoreaz traiectului sinuos de care dispune
deseori artera lienal. Deci traiectul vasului vizat variaz n prim plan n funcie de proprietile
individuale ale subiecilor. Cele menionate prezint careva dificulti n timpul interveniilor
66

chirurgicale n zona respectiv prin faptul c ele trebuiesc cunoscute i luate n calcul n
medicina practic.
Analiza rezultatelor a demonstrat c n 44, 5% din cazuri (36 de observaii) artera
lienal avea un traiect rectiliniar. n 27 de cazuri (33, 3%) traiectul ei era puin sinuos. n alte 18
(22, 2%) cazuri specificul traiectului arterei lienale const n aceea c ea prezenta dou trei
segmente n form de spiral, cu o distan ntre ele de 2 4 cm. Din acest numr de observaii
18, 72,2%, ceea ce constituie 13 cazuri, au fost depistate la persoanele care depise vrsta de 60
de ani. n aa mod, constataia capt statut de legitaie: cu ct vrsta subiecilor este mai
naintat, cu att traiectul arterei lienale devine mai sinuos.
Artera lienal, la originea sa (segmentul incipient) de cele mai multe ori 65 (80,3%)
de observaii, formeaz un unghi ascuit cu trunchiul celiac; n restul cazurilor 16 (19,7%)
unghiul respectiv se apropie de 90.
Sediul topografic al arterei lienale n raport cu pancreasul variaz mult. n majoritatea
cazurilor artera lienal corespunde marginii superioare a pancreasului, avnd o orientare spaial
mai aproape de orizontal. Varianta n cauz a fost nregistrat n 44 (54, 4%) cazuri. n cazurile
n care traiectul vasului dat este sinuos, unele segmente vasculare devin supraiacente
pancreasului. n cazurile n care artera dispune de traiect rectiliniar, topografic, n mare parte ea
corespunde marginii superioare a pancreasulu. Cnd direcia ramificrilor arterei lienale cu
direcia ei pn la ramificare formeaz unghiuri aproape drepte, unele ramificri sunt direcionate
descendent. Frecvena variantei date a constituit 12, 3% (10 cazuri). Artera lienal era amplasat
din posteriorul marginii superioare a pancreasului n 9 (11, 1%) cazuri, iar pe faa anterioar a
corpului pancreatic n 2 (2, 5%) din cazuri. Merit atenie, inclusiv din punct de vedere clinic,
varianta n care artera lienar era ancorat, parial sau n totalitate, n grosimea parenchimului
pancreatic; frecvena variantei n cauz a constituit 16 (19, 7%) observaii din totalitatea
cazurilor.
[6], avnd 850 de observaii proprii, au stabilit c n 95% din cazuri artera lienal,
topografic, corespundea marginii superioare a pancreasului, n restul observaiilor (5,0%) vasul
avea sediu retropancreatic. n 2 (0, 23%) din cazurile analizate de autorii citai vena lienal era
poziionat din faa arterei omonime.
n literatura de domeniu, n aspect aplicativ, artera lienal este descris n funcie de
segmente; ele prezint interes n intervenii chirurgicale pe spin, pe pancreas sau pe nsui
arter. n legtur cu separarea arterei lienale si aplicarea ligaturilor la diferite niveluri, [13]
descriu segmentele proximal, mediu i distal ale vasului n cauz. Sub acelai unghi de vedere,
[10] divid artera lienal n patru segmente relativ bine conturate. Este vorba de: segmentul iniial
urmeaz de la trunchiul celiac pn la corpul pancreasului, cu sediu supraiacent marginii
superioare a pancreasului i o lungime de 2 3 cm. El se afl n grosimea unui strat celular lax
perivascular. Segmentul incipient poate absenta n cazurile n care artera lienal formeaz un
unghi drept cu trunchiul celiac, el avnd traiect paralel i mai sus marginii superioare a
pancreasului.
Printre materialele proprii am nregistrat un caz n care distana dintre trunchiul celiac
i pancreas era foarte mic. Raporturile spaiale erau de aa ordine, nct artera lienal avea
originea n parenchimul glandular. n aa mod, artera era amplasat intraglandular pe un traiect
de 4,5 cm, la o adncime de 1,0 cm n raport cu faa anterioar a organului. Deci separarea
arterei a dus la o distrucie a parenchimului glandular, ceea ce are consecine clinice grave n
intervenii operatorii att pe pancreas, ct i pe artera lienal. Revenind la cazul n descriere,
trebuie menionat c, respectiv corpului pancreasului, artera i vena lienale pe un traseu de 4,0
cm erau ancorate ntr-un nule de sut glandular la nivelul marginii superioare a pancreasului.
La limita dintre corp i coad, artera lienal lanseaz ramura polar inferioar, iar trunchiul
arterial, prinr-o curbur moderat, urmeaz n sens ascendent spre hilul lienal.
Al doilea segment vascular corespunde corpului pancreasului, el are o lungime de 8
10 cm. Sediul arterei lienale difer: el poate fi intrapancreatic, pe feele anterioar sau
posterioar, sau pe marjinea superioar a pancreasului. Separarea arterei de suturile
67

nconjurtoare este dificil, inclusiv din cauza ramusculelor scurte, responsabile de nutriia
glandular, cu att mai mult n cazurile sediului ei intravisceral.
Rezultatele actualului studiu au demonstrat c n 81, 5% din cazuri (66 de observaii)
artera lienal era plasat pe faa anterioar a cozii pancreasului, n timp ce n 16, 0% din cazuri
(13 obiecte) ea era poziionat pe faa posterioar a aceleiai poriuni pancreatice. Mai rar 2,
5% din cazuri (2 observaii), a. lienalis se afla supraiacent la cauda pancreas. Segmentul
respectiv al arterei splenice nu totdeauna este reprezentat de un trunchi unic. Remarcm acest
fapt din considerente clinice, el se refer la modalitatea ramificrii a. lienalis. O alt remarc de
ordin topografic: n unele cazuri primele trei segmente ale arterei lienale sunt poziionate cu 1, 5
cm mai sus de marjinea superioar a pancreasului.
Segmentul prehilar reprezint poriunea a. lienalis dintre coada de pancreas i hilul
lienal. Noi am studiat acest segment vascular pe 111 obiecte. Lungimea lui variaz ntre 1 i 5
cm, fiind amplasat n grosimea ligamentului pancreatolienal. Segmentul prehilar al a. lienalis,
din punct de vedere structural, se caracterizeaz prin prezena multiplelor ramificri ntreesute
cu vase venoase. Referitor la segmentul prehilar [2], relatau c el dispune de lungime medie
egal cu 1,5 cm, care variaz de la caz la caz n limitele 0,3 4,5 cm.
Locul i modalitile de ramificaie ale arterei lienale sunt diferite i variaz mult.
Cercetrile arat c deseori artera se ramific la nivelul cozii pancreasului ori ntre foiele
ligamentului pancreatolienal. Odat cu implicarea chirurgilor n rezecia diferitelor poriuni ale
splinei n caz de traumatisme, maladii benigne i alotransplantri a hemisplinei de la un donator
nrudit viu, foarte esenial a devenit nelegerea diviziunii anatomice a lobilor i segmentelor
acestui organ. Pentru diferite vase i segmente splenice nu exist o nomenclatur unic, se cere
n primul rnd o descriere preliminar.
Artera lienal n 90% din cazuri (100 de obiecte) se ramific dihotomic n ramuri de
ordinul I superioar i inferioar. Prima din ele mai frecvent avea diametrul mai mare, se
ndrepta spre polul superior/posterior ale splinei, iar a doua la polul inferior/anterior.
Unghiurile ramificaiei acestor vase sunt solitar diferite. n 67 (60, 3%) cazuri arterele se
ramificau sub un ungi ascuit i se apropiau de splin n treimea medie a hilului. Mai frecvent
36 (53, 7%) cazuri jumtatea superioar a splinei era vascularizat cu participarea ramurilor
arterei superioare, iar cea inferioar din contul arterei inferioare. n 23 (34, 3%) de cazuri
persista o variant de vascularizare a splinei, cnd artera inferioar vasculariza 2/3 inferioare a
parenchimului organului, iar restul splinei rmnea pe contul arterei superioare. Mai rar, 8 (12%)
cazuri, n 2/3 superioare ale splinei se ramifica artera superioar, iar n 1/3 inferioar artera
inferioar cu ramificaii mai reduse la numr.
Numai n 33(29,7%) de cazuri arterele destul de evident se deviau spre polurile splinei
ramificnduse sub un unghi obtuz. Ramificaia avea loc la o distan de pn la 4 5cm de la
hilul splinei, sau cu formarea unui peduncul scurt n apropierea splinei.
Artera lienal n 8 (7, 2%) cazuri se ramifica n 3 ramuri de ordinul I care urmau ctre
polii i poriunea central a organului.
Clasificarea lobilor i segmentelor splinei este prezentat diferit n literatura de
specialitate. Dup [9], artera splenic se divide n dou ramuri lobare: artera splenic superioar
i artera splenic inferioar, dar nu a fost nregistrat a treia arter lobar.
Numai ntr-un caz (0, 9%) artera lienal era ramificat n 5 artere de ordinul I. Forma
magistral, cnd a. lienalis n hil se ndrepta spre polul inferior, dnd concomitent de la 5 pn la
7 ramuri, a fost nregistrat n 2 (1,8%) cazuri.
O alt abordare de clasificare a ramificaiei arterei lienale are loc n baza ramurilor
vaselor hilare. Artera splenic bifurcat sub un unghi ascuit la distana de hil ntre 3 i 7 cm
capt aspectul literei Y culcat. Aa configuraie a vasului era observat pe majoritatea
pieselor disecate 67 % din cazuri. Numai n 33 % bifurcaia vasului avea loc n apropierea
hilului lienal (distana pn la 3, 0 cm), sub un unghi obtuz. Forma vasului amintea litera T
[8], descriu peduncul splenic scurt (2, 5 3, 0 cm) n 9% din cazuri (10 piese). Artera splenic se
bifurc n apropierea hilului, unghiul dintre cele dou ramuri fiind obtuz, apropiat valorii de
68

180, conferindu-i aspectul literei ,,T. n tipul peduncul lung se ncadreaz arterele splenice
bifurcate la distana de hil ntre 3 i 6 cm. Aspectul ramificrii vasului fiind al unei litere ,,Y
culcat. Aceast configuraie a fost observat la majoritatea pieselor disecate 91% (110 piese).
n 40 (36, 1%) de cazuri de la artera lienal, pn la ramificarea n ramuri de ordinul I
se desprinde o arter care urmeaz la unul din polii splinei. Mai des era ntlnit artera polar
inferioar 21 (52, 5%) de cazuri.
Nemijlocit de la trunchiul arterei lienale ea pornete n 16 (76, 2%) cazuri, iar de la
ramura inferioar de ordinul I n 5 (23, 8%) cazuri. Artera polar inferioar are arhitectur mai
complicat. n 15 cazuri ea pornete printr-un trunchi comun cu artera gastroomental stng. n
3 cazuri avea un trunchi comun cu artera gastroomental stng i cu ramura cozii pancreasului,
i numai ntr-un caz cu ramura splinei accesorii.
Artera polar superioar a fost depistat pe 14 (35%) piese anatomice. Mai des ea se
desprinde de la un trunchi al arterei lienale 11 (78, 5%) cazuri (fig. 29); mai rar 3 (21, 5%)
cazuri de la ramura superioar de ordinul I (fig. 30).
Numai n 5 cazuri (12, 5%) arterele polare se ramifica pentru ambii poli al splinei. Mai
rar 3 cazuri (60 %) arterele polare erau dublate.
Ramurile arterei lienale de ordinul I, II, III, n zona hilului splinei, au diverse raporturi
topografice, care determin aspectul arhitectonic al sistemului vascular arterial. Fiecare din
ramurile primare (de ordinul I) poate s se ramifice dihotomic sau lanseaz 3 4 ramificri de
ordinul II; ele duc la apariia unui complex vascular, de la care, n funcie de particularitile
individuale ale subiecilor, n parenchimul splinei ptrund de la 2 pn la 17 ramuri. De cele mai
dese ori capsula organului este penetrat de 6 10 ramuri arteriale de ordinul II i III. Cele din
urm pot fi asociate i cu ramificri de ordinul IV V. Din aceste considerente ligatura arterei
lienale n zona hilar ntlnete dificulti de ordin tehnic, totodat, scade eficiena ei.
Sistemul vascular al splinei poate fi examinat i prin intermediul panaortografiei. Ea
permite a stabili sursele de vascularizaie ale splinei, traiectul, modul i locul de ramificare a
arterei lienale, inclusiv tipul de ramificaie, corelaiile spaiale cu alte vase ale cavitii
abdominale, traiectul i amplasarea ramurilor arterei lienale de diferit ordin. Informaia de acest
gen prezint interes aplicativ la stabilirea diferitelor procese patologice ale organului.
Panaortografia permite stabilirea pe viu a tuturor jaloanelor sistemului vascular, a variantelor lor
de structur i corelaiile spaiale n parenchimul organului.
n aa mod au fost analizate 106 de panaortograme. Artera lienal a avut traiectul
spiralat n 40 (37, 8%) de cazuri; n 39 (36, 7%) cazuri ea despunea de un traiect rectiliniu. n
alte 25, 5% din cazuri (27 observaii) traiectul a. lienalis era uor sinuos. La 59 (55, 7%) dintre
subieci, n zona hilar artera lienal se ramifica dihotomic; trifurcaia ei a fost stabilit n 19 (17,
9%) cazuri. De remarcat o alt variant: artera lienal ptrundea n parenchimul lienal sub forma
unui singur trunchi, variantei n cauz i-au revenit 28 (26, 4%) cazuri.
Prin analiza angiogramelor autorii [16], au stabilit c n 7, 5% din cazuri a. lienalis
intr n zona hilar sub forma unui singur trunchi; n alte 46% din cazuri ea se bifurc dac nu n
zona hilar, apoi n apropierea ei. Trifurcaia arterei lienale a fost observat n 36% din cazuri,
tetrafurcaia n 4, 8% din observaii. Autorii citai relateaz prezena pentafurcaiei n 4% din
cazuri, iar n 1, 7% artera lienal lansa 6 i mai multe ramuri.
Anastomozele arterei lienale pot fi grupate n intrasistemice i intersistemice. Ele
asigur afluxul sangvin suficient al splinei n cazurile deconectrii trunchiului principal sau a
ramurilor mari. Totodat, mult depinde de locul aplicrii ligaturii arteriale sau de sediul
trombilor sau a altor factori care obstacoleaz circulaia sangvin n zona respectiv.
Rolul anastomozelor intrasistemice ale arterei lienale este mai puin important
comparativ cu anastomozele intersistemice. Analiza materialului propriu ne permite s ne
referim la anastomozele intrasistemice ale arterei lienale. Ele, totodat, se pot forma i cu
participerea ramusculelor cu genez din alte surse arteriale adiacente, devenind concomitent
anastomoze intra- i intersistemice.
69

n zona hilului lienal se formeaz ci circulatorii colaterale; la ele particip ramificri

ale arterei lienale. Chiar i ramurle de ordinul I pot comunica ntre ele. n alt caz artera polar
superioar, cu un diametru relativ mic, unea trunchiul arterei lienale cu ramura ei superioar de
ordinul I. n hilul lienal, arterele de ordinul I pot forma arcade, orientate transversal n raport cu
direcia ramurilor de prim ordin; ele se anastomozeaz cu ramificri de ordinul II III cu genez
din ramura inferioar de ordinal I.
Uneori n regiunea hilului se formeaz arcade care amintesc ansele vasculare
localizate n mezenter.
Anastomozele intersistemice unesc ramurile a. lienalis cu vasele arteriale ale altor
organe, inclusiv a stomacului, pancreasului, duodenului, anselor intestinale, epiploonului mare.
Numrul acestor anastomoze variaz n legtura cu caracterul inconstant al ramurilor arterei
lienale ctre organele vecine. Colaterale se formeaz ntre a. lienalis, sau ramurile ei, i artera
gastroomental stng, gastrice scurte i al. S-au depistat segmente vasculare care formeaz
colaterale, sau arcade, lungi i scurte. Asemenea legturi unesc poriunea distal a a. lienalis cu
ramuri ale arterelor hepatic comun i mesenteric superioar. La formarea colateralei particip
artera cozii pancreasului care se desprinde de la artera lienal n regiunea hilului sau pornete de
la trunchiul spleno-gastro-omental i ramura lienal inferioar de ordinul I.
Artera gastroomental stng cu originea din trunchiul arterei lienale sau de la
ramurile ei, era evideniat pe toate piesele. Artera formeaz colaterale n regiunea curburii mari
a stomacului cu artera omonim din dreapta (de la a. gastroduodenalis).
Arterele gastrice scurte se anastomozeaz cu ramurile arterei splinei; ele au fost
identificate pe toate piesele, n numr de 2 4 ramuri, care urmeaz n componena ligamentului
gastrolienal. Pe dou piese au fost depistate cte 6 artere gastrice scurte. Anastomozele directe,
dei nu totdeauna se evideniaz, se formeaz ntre ramurile gastrice scurte i artera gastric
stng.
Multiplele observaii experimentale i clinice asupra ligaturii arterei splenice n cazul
tratamentului unui ir de boli i deteriorri ale splinei, au confirmat posibilitile largi de
dezvoltare a vascularizaiei colaterale n zona bazinului ei.
A fost stabilit c cea mai important valoare practic pentru pstrarea splinei n cazul
deteriorrii tractului principal al a.lienalis are traectul arterelor gastrice scurte i al arterei
gastroomentale. Dac vom suspenda circulaia prin a.lienalis respectiv hilului splinei i vom
pstra integritatea lig. gastrolienalis cu colateralele gastrolienale incluse n el, nu apare necroza
splinei, deseori n ea nu se ntrevd schimbri vizibile sau exist o atrofiere neesenial a
organului. Comunicrile a. lienalis cu arterele gastrice scurte i artera gastroomental stng n
hilul splinei sau ligatura peduncului lienal cu ligamentul gastrolienal deseori duce la necroza
organului i dezvoltarea peritonitei. De aceea, se consider c ligatura a.lienalis n scopuri de
tratament al hipertensiei portale este corect de efectuat mai proximal de ramificaia colateralelor
amintite, adic la 4 6 cm de la hilul splinei.
Venele splinei nu au atras atenia morfologilor mult timp. Dar n ultimii ani, n
legtur cu evoluarea metodelor diagnostice (spleno-portografia) i a operaiilor n cazul
insuficienei portale, precum i a interveniilor pe pancreas, lacunele au fost suplinite. Venele
extraorganice ale splinei n mare parte urmeaz traiectul arterelor. Ele fuzioneaz, de regul, n
trunchiul solitar vena lienal (v. lienalis), diametrul creia dipete de 1, 5 2 ori calibrul
arterei ononime.
De obicei din hilul splinei se depisteaz 5 6 vase venoase de ordinul II III, uneori
3 4, care fuzioneaz n trunchiuri mai groase de ordinul I. Formarea trunchiului venei lienale
are loc diferit, n dependen de cantitatea i caracterul jonciunii ramurilor ieite din parenchim
i a locurilor lor de contopire. Deseori (90%) vena lienalis este format din 2 vene de ordinul I
superioar i inferioar.
Vena superioar se amplaseaz sub forma unui arc descendent de-a lungul axei
longitudinale a splinei. Afluenii ei sunt ramurile de ordinul II de la 1 pn la 6. Vena inferioar
este situat orizontal, sau se ridic oblic n sus, primind 2-3 ramuri de ordinul II. n 7, 2% din
70

cazuri vena lienalis, n apropierea hilului splinei, este format din 3 ramuri venoase, 2 dintre care
vin de la poluri i una din centrul organului. Uneori (0, 9%) poate avea loc formarea venei
lienale prin fuzionarea a 5 vene, dou dintre care dreneaz partea central. n 1, 8% din cazuri
vena lienal era format n regiunea polului superior, trecea pe faa visceral a splinei, cu
formarea unui arc spre hilul organului. n vena lienal se vrsa 5 6 vene de ordinul I.
Locul de confluere al ramurilor primare i formarea venei lienale poate varia mult de
la caz la caz; mai frecvent aceasta are loc la distana 3 5 cm de la hilul splinei, dar ntr-un ir de
cazuri aceast distan este neglijabil i constituie 0, 5 2 cm. n alte observri fuzionarea
venelor lienale extraviscerale poate avea loc la distana de 7 7, 5 cm de la splin.
n cazuri cnd trunchiul venei lienale este foarte scurt, este greu sau practic imposibil,
ca el s fie utilizat la formarea anastomozei spleno-renale n caz de insuficien portal. Condiii
mai bune pentru ndeplinirea operaiei de acest gen sunt create n cazurile cnd n regiunea
hilului splinei lipsesc venele de ordinul I II iar trunchiul gros al venei lienale i face apariia
din parenchimul splinei [14]. Lungimea venei lienale echivaleaz cu 8 12 cm; calibrul 6 12
mm. n majoritatea observaiilor trunchiul venei lienale i ramurile lui de ordinul I urmeaz de la
stnga spre dreapta, ntre foiele peritoneale ale ligamentului frenicolienal.
n unele cazuri, cnd coada pancreasului este situat foarte aproape de hilul splinei, venele trec
pe faa anterioar a cozii glandei. Apoi vena lienal trece prin incisura marginii superioare a
corpului pancreasului ntr-un anule, dup colul pancreasului, unde se unete cu vena
mesenteric superioar, formnd vena port. Traiectul venei lienale este rectiliniu cu formarea
unei curbe uoare.
Topografic pot fi evideniate 3 poriuni a venei lienale: proximal, mijlocie i distal.
n 66, 7 % din cazuri vena era de la nceput situat pe marginea superioar a corpului i cozii
pancreasului. Locull fuziunii ei cu vena mesenteric superioar era acoperit de colul pancreasului
parial sau complet. Sunt cazuri cnd vena trece mai jos de marginea superioar a glandei,
urmnd pe feele anterioar sau posterioar ale corpului pancreasului, iar porinea distal
corespunde mijlocului lungimii corpului pancreatic. Splina accesorie reprezint o malformaie
congenital ce se caracterizeaz prin esut splenic ectopic separat de corpul splinei [3]. Prezena
acestei malformaii a fost constatat n 10% 30% cazuri la necropsii i n 45% 65% cazuri
dup splenectomie [5].
Splina accesorie se dezvolt din cauza fuziunii incomplete a primordiilor
mezenchimale de dezvoltare a splinei, fiind n totdeauna localizate n partea stng a
abdomenului din cauza rotaiei splinei spre stngaa n timpul embriogenezei. Dimensiunile
splinei accesorii, de regul, variaz de la inluziuni mici microscopice pn la un diametru de 2-3
cm. Cele mai frecvente localizri ale splinei accesorii sunt hilul splinei (75%), coada
pancreasului (20%), artera splenic, ligamentele gastrosplenic, splenocolic i gastrocolic. Foarte
rar splinele accesorii pot fi localizate n mezou, ligamentul splenorenal, epiploon, peretele
jejunului, intrahepatic, sau n regiunea presacral, n scrot, mediastin. Splinele accesorii pot fi
solitare sau multiple, vascularizate cu ramuri ce pornesc de la artera splenic [3].
Fenomenul splinei accesorie a fost studiat pe un lot de 68 macropreparate (26 (38,
29, 53%) au fost de genul feminin i 42 (61, 87, 49%) de genul masculin (< 0,05). La femei
splina accesorie a fost depistat n 4 (22, 7%) cazuri, iar la brbai n 2 (4, 8%).
Preparatele luate de la femei n dependen de vrst au fost repartizate n felul
urmtor: 36-55 ani 26, 9% (7 cazuri), 56-74 ani 50, 0% (13 cazuri), iar n grupa 79-90 de ani
23, 1% (6 cazuri). Este necesar de menionat c splina accesorie (n = 4) a fost depistat numai
n grupa 56-74 ani.
ntre brbai cea mai mare parte din macropreparate 52, 4% (22 cazuri) sunt din
grupa de vrst 36-60 ani, ntre care 1 preparat cu splina accesorie. Partea pentru grupa de
vrst 61-74 ani constitue 19, 0 % (8 cazuri), din care 1 cu splina accesorie, i 16, 7% (7
cazuri) n grupa de vrst 75-90 ani.
n structura macropreparatelor de la brbai pn la vrsta 35 ani (5 cazuri): cte 2, 4%
- nou-nscuii i vrsta 17-21 ani, i 7, 1% n grupa de vrst 22-35 ani.
71

ntre foiele ligamentului frenicolienal era depistat un caz de splina accesorie cu

urmtoarele dimensiuni: 3,5 x 2,5 x 0,5 cm lungimea, limea i grosimea, cu parametrii
organului principal: 11,0 x 7,5 x 1,2 cm. Vascularizarea organului principal se realiza printr-o
ramur independent care se desprindea de la artera segmentar superioar
ramura arterei
lienale. Diametrul vasului arterial al splinei suplimentare corespundea diametrului arterei
segmentare.
ntr-un alt caz splina accesorie avea dimensiunile unei alune fiind localizat n esut
adipos la coada pancreasului, dar dimensiunile organului principal erau 12,0 x 8,0 x 4,0 cm.
Vasul arterial care o alimenteaz, reprezint un ram al arterei polare anterioare ale arterei lienale.
Diametrul arterei splinei accesorii era egal cu diametrul arterei polare anterioare. La ieire, vena
splinei accesorie se unea cu vena polar inferioar a splinei materne i se revrsa n vena
splenic. Inervaia splinei accesorie era asigurat de fibre i fascicule nervoase din plexurile
pancreatic i lienal.
n al treilea caz splina suplimentar avea dimensiunile unui bob i era suspendat de
un peduncul lung. Organul era localizat lng polul anterior al splinei materne care avea
urmtoarele dimensiuni: 13,5 x 10,0 x 4,2 cm. Vascularizarea organului se realiza suplimentar
printr-un vas independent ramura arterei lienale. Pn la hilul splinei accesorii artera se
ramifica n dou vase, care, cu fasciculele nervoase ale plexului lienal, ptrundeau n
parenchimul organului. Din splina suplimentar ieea un vas venos care, nainte de a se vrsa n
vena splenic, se bifurca.
Pe faa posterioar a ligamentului gastrolienal a fost depistat o splina accesorie cu
demensiunile 3,02,51,8 cm, parametrii organului principal constituind 10,2 x 7,0 x 2,2 cm.
Acest organ suplimentar era vascularizat de o ramur independent a arterei lobare posterioare,
fiind inervat de ramuri ale plexului lienal. Vena splinei suplimentare n cauz se vars n vena
lobar posterioar ale venei lienale.
n alt caz de splin suplimentar era situat n esutul adipos al ligamentului gastrolienal. Organul avea peduncul lung, dimensiunile 2,0 x 1,5 x 0,5cm i era localizat la polul
posterior al splinei materne cu parametrii 19,0 x 9,3 x 2,8cm. Vasul arterial al splinei accesorii se
ramifica de la artera lobar posterioar ramura arterei lienale. Vena n cauz se vars n vena
lobar posterioar. Organul suplimentar era inervat de ramuri ale plexului lienal.
Forma rotund de splin suplimentar era situat n ligamentul frenicolienal. Organul
avea dimensiunile 2, 2 x 1, 8 x 0, 6 cm. Parametrii splinei principal erau 20, 0 x 10, 0 x 3, 5 cm.
Splina suplimentar era vascularizat de ramura arterei lobare anterioare. Din organ ieea un vas
venos care se vrsa n vena lobar - ramura venei lienale. Vasele erau nsoite de nervii plexului
lienal.
Analiza statistic a frecvenei cazurilor de splin accesorie a fost efectuat n baza
tomografiei computerizate. Rezultatele obinute au fost analizate n dependena de
particularitile de vrst i genul pacienilor.
Din 257 de pacieni cu tomografia computerizat ale organelor cavitii abdominale la
79 a fost depistat splina accesorie. Din numrul total de pacieni 4 au avut cte 2 spline
accesorie i la 2 pacieni erau depistate cte 3 organe suplimentare. Frecvena splinei accesorie
este de 30, 72, 88% de cazuri.
n funcie de gen cota splinelor accesorii la brbai 57, 0% i la femei 43, 0%. Au
fost stabilite diferenele semnificative statistice (p < 0,001) n funcie de numrul splinelor
accesorii la pacieni n funcie de sex n grupele de vrst VIII1, IX. n grupa IX splinele
accesorii la femei se ntlnesc de 4 ori mai des dect la brbai.
De regul, splinele accesorii corespund, prin structura lor histologic i prin
anghioarhitectura, splinei materne. Ele sunt capabile, n anumite condiii particulare, s exercite
funcii fiziologice, proprii splinei principale. Lund n consideraie variantele dezvoltrii
ontogenetice ale splinei putem constata c splina accesorie cu sistemele ei nervos i vascular
poate fi tratat ca o unitate structural-funcional separat la nivel macromicroscopic.
72

Concluzii
1.Splina este inervat de ctre nervii plexurilor lienal i pancreatic i vascularizat prin ramurile
arterei lienale.
2.Att structural, ct i topografic, artera lienal se evideniaz printr-o gam de variante. Ele se
refer la traseul ei extraorganic, precum i la arhitectonica sistemului vascular intravisceral.
Metoda macroscopic de disecare a demonstrat c traiectul rectiliniu al arterei lienale se
ntlnete mai frecvent 44,5% din cazuri, iar mai rar vasul respectiv era uor sinuos 33,4%
din cazuri.
3.Artera lienal mai frecvent este localizat pe marginea superioar a pancreasului (54,4% din
cazuri).
4. Prin rezultatele analizei panaortogramelor artera lienal era bifurcat n 54, 4% din cazuri.
5.n majoritatea cazurilor constitueni ai venei lienale sunt dou vene de ordinul I.
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infraction: report of three cases of atherosclerotic embolization originating in the aorta and
retrospective study of 64 cases. Acta Clin Belg. 1996; 51: 395-402.
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acute abdomen in children and review of literature. J. Pediatr. Surg. 2009. 44:E15-E18.
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73

NERVUL TERMINAL
(Revista literaturii)
Ion Artene
(Conductor tiinific : dr. conf. Teodor Lupacu)
Catedra Anatomia Omului USMF
Summary
The terminal nerve
The terminal nerve, also called ,, cranial nerve 0 , is the foremost cranial nerve. It looks
like a microscopic ,sympathetic nerve plexus ( J.F. Huber). The nerve is distributed in the
subarachnoid space which covers the gyrus rectus , and in the mucous membrane of the olfactory
area . The presence of the terminal nerve is a certitude, first stated by Dr. Johnston in 1913 and
further confirmed by other researchers .
Peripheral distribution and central connections of the nerve with the limbic system prove
its implication into the mechanism of olfaction in which has a modulatory role.
Rezumat
Nervus terminalis, numit i ,, nervul cranian zero , este cel mai anterior nerv cranian. El
apare sub forma unui plex nervos microscopic, simpatic (J.F. Huber), cu directie centrifugal de
propagare a impulsurilor, distribuit n spaiul subarahnoidian ce acoper girusul rect, precum i
n mucoasa ariei olfactive. Prezena nervului terminal la om este o certitudine, semnalat pentru
prima dat n anul 1913 de ctre Dr. Johnston, i ulterior reconfirmat de mai muli exploratori.
Distribuia periferic i conexiunile centrale ale nervului terminal cu sistemul limbic,
demonstreaz implicarea lui n mecanismele olfaciei n calitate de modulator.
Nervul terminal este mult mai fin dect restul nervilor cranieni, deaceea, n majoritatea
cazurilor, el este nlturat n timpul autopsiilor. Depistarea nervului, fr o coloraie special,
este foarte dificil din cauza dimensiunilor lui foarte mici (comparabile cu cele ale unui fascicul
de colagen) i fuzionarea acestuia cu filetele nervului olfactiv.
Cu toate c nervul terminal este foarte apropiat de nervul olfactiv i este de cele mai multe
ori confundat cu o ramur de-a acestuia, el are origine diferit i nu este conectat cu bulbul
olfactiv [5,9].
Datele raportate se bazeaz pe diseciile efectuate la fetui cu vrsta ncepnd cu 10
sptmni i la nou-nscui, precum i la persoane adulte. Nervus terminalis a fost identificat n
toate cazurile examinate.
Poriunea intracranian a nervului terminal, ncepe n regiunea trigonului olfactiv [6,15],
i se ntinde n direcie anterioar peste suprafaa medial a tractului i bulbului olfactiv, pe
suprafaa lateral a crestei de coco pentru ca mai apoi s abandoneze cavitatea craniului prin
orificiile anterioare ale lamei cribriforme. n cursul su peste suprafaa medial a tractului
olfactiv, nervul se prezint ca un fascicul de fibre nervoase condensate, mai nchise la culoare
dect fasciculele colagene ale meningelui cerebral. Pe faa medial a bulbului olfactiv, fasciculul
se ramific formnd un plex de fibre care se ntreptrund cu fila olfactoria. La nivelul punctelor
de ramificare ale plexului se formeaz civa microganglioni. Unul dintre acetea, format la
nivelul la care nervul terminal se ncrucieaz cu nervul vomeronazal, este mult mai mare dect
restul, fiind numit ganglionul terminal [6,9]. Plexul se extinde pe faa lateral a crestei de coco ,
implantat fiind n pahimeninge. n acest loc, filamentele separate ale plexului nervului terminal
sunt situate la o anumit distan ( variabil, dar corelat cu nlimea crestei de coco) deasupra
plcii cribriforme, spre deosebire de fila olfactoria care se plaseaz direct pe ea.
Dup ce n interiorul cavitii craniului nervul terminal ader la fila olfactoria i la nervii
vomeronazali, acesta trece n mucoasa nazal mpreun cu ei.
Majoritatea fibrelor plexului intracranian al nervului se reunesc ntr-un singur fascicul,
care iese din lama cribriform anterior de nervii vomeronazali. Fibrele regrupate n fascicul,
74

dup ce ajung n cavitatea nazal, traverseaz poriunea antero-superioar a mucoasei septului

nazal, anterior de nervii vomeronazali. n partea superioar a traiectului intranazal, acest fascicul
al nervului se unete cu un filament mic desprins de la ramura medial nazal a nervului etmoid
anterior. Ulterior, fasciculul intranazal al nervului se mparte n 3 ramuri, care tind s se apropie
de organul vomeronazal, dar nu ajung pn la acesta [16].
Fibrele plexului intracranian situat pe faa lateral a crestei de coco, care nu s-au
condensat n fasciculul sus-menionat, trec prin placa cribriform mpreun cu fila olfactoria i se
ndreapt spre mucoasa olfactiv.
Cercetrile demonstreaz c nervul terminal inerveaz epiteliul olfactiv al mucoasei
[8,10], glandele olfactorii ( Bowman) [6,10] i un ir de vase sanguine din mucoasa septului
nazal [6] .
n ceea ce privete conexiunea nervului cu formaiunile encefalului, aceasta se realizeaz
la nivelul poriunii antero-mediale a trigonului olfactiv, ramificndu-se, n prealabil, n dou
ramuri.
Studiile bazate pe metode imunohistochimice, prin evidenierea GnRH ( factor eliberator
de gonadotropine) dar i a altor substane din componena nervului, sintetizate doar de anumite
regiuni ale creierului, demonstreaz legturlie multiple (similare la mamifere) ale nervului cu
structurile encefalului. Astfel, nervul terminal se conecteaz cu o serie de formaiuni ale
sistemului limbic, i nu numai: ariile preoptic i cea suprachiasmatic, nucleii supraoptici,
nucleii ariei hipotalamice laterale, tuberculul cenuiu, nucleul arcuat, nucleii din componena
striei terminale, nucleii habenulei, epifiza [7,17].
Fibrele nervoase ce aparin nervului terminal sunt nvelite de un numr mare de celule
gliale, identice cu cele din fila olfactoria, lipsind ns celulele Schwann. Aceste celule gliale dau
o culoare mai nchis fascicului nervos, dect cea a fasciculelor conjunctive meningeale. Poate
c cea mai co1ncludent dovad c avem de a face cu un nerv i c acesta este nervus terminalis,
este prezena de celule ganglionare caracteristice numai pentru aceast formaiune [6]. Celulele
sunt similare la majoritatea, dac nu la toate vertebratele descrise pn n prezent [2]. La nivelul
microganglionilor nervului, celulele ganglionare formeaz grupuri cte 2-3, numrul de grupuri
fiind de 30 n majoritatea cazurilor.
ntreaga lime a nervului este de aproximativ 0.1-0.3 mm [16]. n unele cazuri
dimensiunile grupurilor ganglionare sunt similare celor ale grosimii fibrelor, la fel cum are loc
la diferite vertebrate [2]. n toate cazurile, a fost remarcat o capsul de celule n jurul neuronilor
ganglionari, n rest fibrele nervoase sunt nvelite de teci gliale clasice pentru fibrele amielinice.
Conform datelor obinute de Wirsig-Wiechmann n anul 2002, fibrele nervului conin
acetilcolin i cteva neuropeptide.
Iniial funcia nervului era considerat ca fiind de percepie a feromonilor. Ulterior
aceast ipotez, bazat pe dispoziia anatomic a nervului (intracranian n apropiere de
sistemul limbic, implicat n reglarea comportamentului, ct i extracranian n apropiere de
organul vomeronazal i contopirea pe alocuri cu nervii vomeronazali) a fost infirmat.
O alt ipotez privind funcia nervului zero vizeaz implicarea acestuia ntr-un mechanism
feedback de reglare a sensibilitii olfactive. Ea se bazeaz pe faptul c creierul vertebratelor
filtreaz activ informaia senzorial recepionat, focusnd atenia spre stimulii mediului care
sunt mai relevani pentru comportamentul animalului ntr-un anumit context social sau stare
psihologic. O asemenea modulare centrifugal s-a dovedit a fi esenial n recepia vizual i
auditiv. n acest context, se consider c nervul terminal moduleaz activitatea epiteliului
olfactiv. Cea de-a doua ipotez a fost confirmat experimental.
Biologii Dr. Park i Dr. Eisthen, n anul 2003, au demonstrat direcia centrifugal de
conducere a impulsului nervos prin fibrele nervului terminal, i capacitatea nervului de a modula
stimulul determinat de un excitant cu intensitatea mai mic sau mai mare dect bariera de
recepie a celulei olfactive [9].
Utilizindu-se diferite tehnici citochimice, s-a demonstrat prezena abundent n fibrele
nervului a neuropeptidei Y. Aa cum neuropeptida Y este implicat n reglarea apetitului i a
75

senzaiilor de foame, s-a cercetat posibilitatea ca nervul s moduleze activitatea epiteliului

olfactiv n dependen de nivelul de foame al animalului. Rezultatele au artat c fibrele nervului
elimin neuropeptida Y numai n caz de foame, aceasta fiind corelat cu apariia n aceast stare,
a receptorilor pentru acest neuropeptid pe celulele olfactive. Datele obinute demonstreaz faptul,
c nervul prin intermediul unor neuropeptide mrete sensibilitatea celulelor olfactive pentru
mirosurile referitoare la hran, atunci cnd animalul este flmnd; iar prin alte neuropeptide
supreseaz rspunsul la aceleai mirosuri, atunci cnd acesta depete starea de foame [13].
Multitudinea de neuropeptide cu efect antagonist unele mresc, altele reduc sensibilitatea
celulelor olfactive pentru un anumit grup de substane- (de exemplu: GnRH blocheaz
mirosurile referitoare la mncare ntlnite [12]; SP regleaz reflexul vomei, diminund
sensibilitatea la anumite mirosuri [1] ) , par a fi implicate n modularea sensibilitii epiteliului
olfactiv n diferite contexte. Aceste fenomene sunt influenate de sistemul limbic, cu care nervul
este conectat, pentru a determina un anumit comportament avantajos, adecvat strii
organismului.
Nervul terminal pare a avea i aciune de reglator al presiunii sanguine, innd cont de
substanele depistate (VIP, CGRP) [11], dar i de distribuirea terminaiunilor axonice n pereii
unor vase sanguine [6].
Experimentele efectuate pe animale, demonstreaz c nervul are o activitate secretorie
ciclic (n perioada reproductiv, neuropeptidele nervului terminal cresc pragul de sensibilitate
pentru mirosurile asociate hranei, pentru a concentra atenia individului spre ademenirea
partenerului [14] ).
Nervul terminal este o parte component a sistemului limbic , intervenind n modularea
recepiei olfactive n vederea adaptrii organismului la condiiile schimbtoare ale mediului,
printr-un rspuns adecvat la stimuli chimici de intensitate diferit.
Bibliografie
1. Bouvet J. F., Delaleu J.C., Holley A. The activity of olfactory receptor cells is affected by
acetylcholine and substance P. Neurosci Res 1988, 5:214223. [PubMed: 2451792]
2. Johnston N. B., 1913. Nervus terminalis in reptiles and mammals. Jour. Comp.Neur., vol. 23,
no.
3. Huber G . Carl and Guilt, Stacry. 1913 Observations on the peripheral distribution of the
nervus terminalis in Mammalia. Anat. Rec., vol.7, no. 8, p. 253.
4. Brookover C .1 914 The nervus terminalis in adult man. Jour. Comp. Neur., vol. 24, p.131.
5. Demski L.S., Schwanzel-Fukuda M., 1987. The terminal nerve (nervus terminalis). Structure,
function and evolution.
6. Demski L.S., 1993. Terminal nerve complex. Acta Anat., 148:8195.
7. Larsell O. 1918. Studies on the nervus terminalis: mammals. J Comp Neurol 30:3 68.
8. von Bartheld CS. 2004. The terminal nerve and its relation with extrabulbar olfactory
projections.
9. Wirsig-Wiechmann CR, Wiechmann AF,Eisthen HL. 2002. What denes the nervus
terminalis? Neurochemical, developmental, and anatomical criteria. Prog Brain Res 141:45- 58
10. Marilyn L. Getchell Ph.D., 1992 , Fine structural aspects of secretion and extrinsi innervation
in the olfactory mucosa p. 111-127.
11. Thomas V. Getchell and Marilyn L. Getchell, 1990, Regulatory factors in the vertebrate
olfactory mucosa p.223-231.
12. Heather L. Eisthen, Rona J. Delay, Celeste R. Wirsig-Wiechmann ,and Vincent E.Dionne;
Neuromodulatory effects of Gonadotropin Releasing Hormone on olfactory receptor neurons
J. Neurosci. 1 June 2000: 3947-3955.
13. Angela Mousley, Gianluca Polese, Nikki J. Marks, and Heather L. Eisthen ,Terminal nervederived neuropeptide Y modulates physiological responses in the olfactory epithelium ; J.
Neurosci. 19 July 2006: 7707-7717.
14. Takafumi Kawai ,Yoshitaka Oka and Heather Eisthen , The Role of the Terminal Nerve and
76

GnRH in Olfactory System Neuromodulation ; Zoological Science 26: 669680 (2009).

15. Fuller G.N., Burger P.C. (1990). "Nervus terminalis (cranial nerve zero) in the adult human".
Clin. Neuropathol. 9 (6): 279283.
16. Rollo E. McCotter ; A note on the course and distribution of the nervus terminalis in man ;
Anatomical Record . vol. 9, n o. 3.
17. Helmut A. Oelschlger, R. Glenn Northcutt, Immunocytochemical localization of luteinizing
hormone-releasing hormone (LHRH) in the nervus terminalis, The Journal of Comparative
Neurology, vol. 315, n o. 3,15 January 1992: 344-363.

NERVUL SAFEN I LEZIUNILE LUI N CAZ DE STRIPPING AL VENEI SAFENE

MARI (revista literaturii)
Anastasia Bendelic
Catedra Anatomia omului, USMF Nicolae Testemianu
Summary
Saphenous nerve and its lesions after stripping of great saphenous vein
Many patients undergo a stripping operation, saphenous nerve injury is a significant
postoperative complication. Symptoms of nerve injury sometimes continue for a long time, and
are thus not negligible. Lesions of saphenous nerve is characterized with the triad of anesthesia,
hyperesthesia, and pain along the medial side of the calf and foot to the level of the great toe.
The anatomical relationship between the saphenous nerve and the great saphenous vein is varied
and the two structures run close to each other so a better knowledge of their anatomy in itself
proved insufficient in preventing damage to the saphenuos nerve.
Rezumat
Muli pacieni supui unei operaii de stripping prezint o complicaie frecvent lezarea
nervului safen. Semnele lezrii nervului uneori persist pentru un timp ndelungat i nu pot fi
neglijate. Lezarea nervului safen se caracterizeaz prin triada de simptome: anestezie,
hiperestezie i durere de-a lungul feei mediale a gambei i piciorului pn la degetul mare.
Raporturile dintre vena safena mare i nervul safen sunt foarete variate, aceste dou structuri
fiind situate foarte aproape una de alta, iar cunotinele despre anatomia lor sunt insuficiente
pentru a preveni lezarea nervului.
Patologia sistemului venos afecteaz 30-50% din populaia adult a globului, fiind o
important cauz de morbiditate [15], iar rata mereu crescnd a sindromului posttromboflebitic
(4,7% -7,8%) cu un procent nalt de invalidizare n categoria persoanelor apte de munc [26], o
poziioneaz astzi printre prioritile de cercetare.
Flebologia, considerat mult timp o cenureas a specialitilor medicale, este la ora
actual relansat prin progresele aduse prin cercetare, medicin bazat pe dovezi i tehnic de
investigaie diagnostic noninvaziv [7, 23].
Implimentarea metodelor performante de studiere a fluxului sanguin cum ar fi ultrasonografia
Doppler duplex [4, 14, 15, 25, 26] etc., permite stabilirea unui diagnostic mai corect i alegerea
unei tactici terapeutice adaptate perfect fiecrui caz.
Varicele sunt dilataii permanente i neregulate ale venelor. Ele sunt cel mai adesea, tortuoase
i sediul unui reflux sanguin. Dei, n principiu, orice ven ar putea deveni varicoas, n practic
varicele sunt localizate, de regul, n jumtatea inferioar a corpului, preponderent la nivelul
membrelor inferioare i atunci intereseaz, mai ales, venele subcutanate.
De-a lungul timpului interesul crescut pentru aceasta patologie, a dus att la perfecionarea
metodelor de diagnostic, ct i a modalitilor terapeutice. Pentru stabilirea unui diagnostic ct
77

mai corect i alegerea metodei terapeutice adaptat perfect fiecarui caz se utilizeaza flebografia
i ultrasonografia Doppler pentru verificarea permeabilitii sistemului venos profund i
evaluarea venelor perforante.
Metodele terapeutice chirurgicale utilizate n tratamentul insuficienei venoase cronice sunt:
safenectomiile prin stripping, flebectomiile si crosectomiile, asociate cu tratament antiinflamator,
flebotonic etc. [2, 3, 8].
Muli pacieni supui unei operaii de stripping prezint o complicaie frecvent lezarea
nervului safen [1, 5, 9, 10, 16, 20, 21, 24]. Semnele lezrii nervului uneori persist pentru un
timp ndelungat i nu pot fi neglijate. n literatura de specialitate incidena lezrii nervului safen
dup un stripping total este destul de variabil, de la 6-7 % [10] pn la 58 % [16], iar efectul
acestei lezri asupra calitii vieii nu este adecvat studiat.
Dup Nair i coautorii [18] semnele lezrii nervului safen sunt prezente n 90 % cazuri ndat
dup stipping i persist n 10% cazuri peste 14 - 18 luni dup intervenie. Semnele acestei lezri
pot afecta calitatea vieii n 6,7 % din cazuri [16]. Manifestrile lezrii nervului safen sunt de
cele mai dese ori subiective, iar metode obiective de evaluare a acestei traumatizri nu au fost
stabilite, cu mici excepii [1].
Semnele lezrii nervului safen sunt: amoreal, furnicturi, dureri, anestezie. Localizarea
tipic a durerii este pe faa medial i inferioar a gambei. Alte simptome de asemenea prezente
sunt: hipoestezie, parastezie i hiperestezie.
S-a observat c strippingul selectiv a venei safene mari reduce incidena de traumare a
nervului safen [9, 20], dar un alt raport arat c nu este nici o diferen ntre strippingul total i
cel selectiv.
Ramasastry i coautorii [20] au demonstrat c strippingul n direcie cranial (disecia ncepe
de la maleola medial i continu cranial) este nsoit de schimbri senzitive semnificative n
teritoriul senzitiv al nervului safen pe parcursul a 12 sptmni postoperatorii consecutiv n
raport cu strippingul n direcie caudal (disecia ncepe cu jonciunea safenofemural i
continu caudal). La 6 luni de la stripping, ns, rezultatele erau similare. Dup un studiu efectuat
pe cadavre [20] autorii au concluzionat c n timpul strippingului n direcie cranial smulgerea
ramurii pretibiale i/sau ramurii infrapatelare se ntlnete mult mai frecvent dect n strippingul
n direcie caudal.
O metod, care ar elimina complicaia dat la moment nu a fost raportat, probabil, fiindc o
metod de evaluare obiectiv a lezrii nervoase nu a fost stabilit, iar simptomele traumrii
nervului safen sunt doar subiective.
Cunoaterea anatomiei nervului safen este un criteriu indispensabil pentru stabilirea unor
asocieri obiective ntre simptomatologia cu care se confrunt clinicienii n practic i substratul
morfologic.
Nervul safen este o ramur a nervului femoral, care la rndul su, este un nerv mixt, constituit
din unirea ramurilor anterioare ale nervilor spinali L2, L3 i L4 la nivelul bazinului ntre marginea
extern a psoasului i muchiului iliac.
Nervul femural merge sub ligamentul inghinal, lateral de vasele femurale i ajunge n
triunghiul Scarpa, unde se divide n numeroase ramuri care diverg n toate sensurile [12, 22, 27,
28]. El d ramuri colaterale i ramuri terminale [12, 13, 29].
Ramurile colaterale ale nervului femural apar pe traiectul intrapelvin a nervului i se distribuie
muchiului psoas mare, muchiului iliac i muchiului pectineu [12, 13] i o ramur pentru
artera femural [29].
Ramurile terminale prezint un teritoriu motor i altul senzitiv.
Teritoriul motor este reprezentat de ramurile musculare, ce se distribuie la muchii sartorius,
pectineu i adductor lung i cvadricepsului femural.
Teritoriul senzitiv este reprezentat de ramuri cutanate (rr. cutanei femoris anteriores) i
nervul safen (n. saphenus). Acetia inerveaz tegumentul prii anterioare a coapsei, prii
78

interne a genunchiului, tegumentul feei interne a gambei, regiunii maleolare, marginii mediale a
plantei pn la baza primului metatarsian [12, 22, 27, 29].
Dup ali autori [6, 12] nervul femoral se divide n 4 ramuri terminale, dispuse n dou
straturi, superficial (nervul musculo-cutanat extern i nervul musculo-cutanat intern) i profund
(nervul cvadricepsului i nervul safen):
nervul musculo-cutanat extern, care se distribuie muschiul croitor i senzitiv feei externe
a coapsei i interne a genunchiului;
nervul musculo-cutanat intern, ce inerveaz muchii pectineu i adductor lung i senzitiv
regiunea antero-intern a coapsei;
nervul cvadricepsului ce se divide n ramuri, pentru fiecare din cele patru poriuni
constituiente ale muchiului cvadriceps: vast medial, vast lateral, vast intermediar i
drept femoral;
nervul safen este, de fapt, o ramur senzitiv pentru faa medial a gambei i a regiunii
anterioare a rotulei.
Nervul musculo-cutanat extern este un nerv ce se divizeaz n ramuri musculare i cutanate.
Ramurile musculare n numr variabil sunt destinate muchiului croitor, iar cele cutanate sunt n
numr de trei: ramura perforant cutanat superioar, ramura perforant cutanat medie i
ramura cutanat accesorie a venei safene mari [6]. Ramura cutanat accesorie se divide n dou
ramuri secundare: una superficial, alta profund. Ramura superficial este ramura satelit a
venei safene interne, penetreaz muchiul croitor, nsoete vena safena mare pn la faa intern
a genunchiului. Ramura profund e ramura satelit a arterei femurale, nsoete artera pn n
canalul Hunter i se ramific pe faa intern a genunchiului. Cele dou subdiviziuni ale ramurii
cutanate accesorii anastamozeaz cu terminaiile sale cu ramura cutanat a nervului obturator i
nervul safen [6].
Nervul musculo-cutanat intern se divide de la originea sa n ramuri musculare i cutanate.
Ramurile musculare n numr variat de la 1 la 3, traverseaz oblic faa posterioar a vaselor
femurale i inerveaz muchiul pectineu i muchiul adductor lung. Ramurile cutanate sunt i
ele n numr variabil; cnd sunt dou ramuri, una trece anterior, a doua posterior de vasele
femurale, se unesc lateral de arter ntr-o ramur unic, traverseaz fascia lata i se ramific pe o
poriune mic n partea supero-intern a coapsei. O ramur care trece anterior de vase poate
exista singur [6].
Nervul cvadricepsului cedeaz patru ramuri, care sunt destinate celor patru pri ale
quadricepsului: rectului femoral, vastului lateral, vastului medial i vastului intermediar [6, 12].
Nervul safen este situat lateral de vasele femurale i este nsiit de nervul vastului medial. n
partea inferioar a triunghiului Scarpa nervul penetreaz teaca vaselor femurale, apoi descinde
de-a lungul arterei femurale pn la extremitatea inferioar a canalului Hunter. Pe traiectul su
nervul safen se plaseaz succesiv n faa, apoi n spatele arterei. Nervul safen traverseaz lamela
fibroas vastoadductorie a canalului Hunter, poate singur, sau poate nsoit de ramura
descendent a genunchiului de la artera femural. Dup ce perforeaz fascia coapsei se mparte
n ramuri terminale: ramura rotulian (infrapatelar) i ramura crural sau ramura cutanat
medial a gambei.
Ramura infrapatelar sau rotulian cedeaz numeroase ramificaii divergente pe faa
anterioar a genunchiului; cnd ncepe foarte nalt de la nervul safen, devine superficial,
perfornd muchiul croitor i constituie a treia ramur perforant sau ramura cutanat perforant
inferioar [6, 12].
Ramura crural nsoete vena safena mare i se distribuie ntr-un numr de ramuri cutanate
pe faa intern a gambei. Raporturile dintre vena safena mare i nervul safen sunt foarete variate,
aceste dou structuri fiind situate foarte aproape una de alta, iar cunotinele despre anatomia lor
sunt insuficiente pentru a preveni lezarea nervului [11, 19]. Vena safena mare trece de-a lungul
nervului safen n 59,5 % cazuri n treimea medie a gambei i 83,1 % n treimea inferioar a
79

gambei [17]. n mai mult de 50 % cazuri s-a demonstrat c perineurium nervului safen este fixat
de adventiia venei [17]. Ramura crural se termin pe faa antero-intern a gleznei, maleolei
mediale i marginea medial a piciorului.
Lezarea nervului safen este urmat de tulburrile de sensibilitate obiectiv, limitndu-se la
teritoriul senzitiv inervat, anestezia interesnd faa intern a gambei.
Cunoaterea interrelaiilor dintre nervul safen i vena safena mare ar putea reduce incidena
lezrii nervului intraoperator.
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24. Wood JJ, Chant H, Laugharne M, Chant T, Mitchell DC. A prospective study of cutaneous
nerve injury following long saphenous vein surgery. European Journal of Vascular and
Endovascular Surgery, 2005, vol. 30, p. 654-658.
25. Zaporojan A., Casian D., Moroz S., Culiuc V. Flebotrombozele acute iliofemorale. Arta
Medica, N4 (25), Chiinu, 2007, p. 18.
26. Znoag M., Spnu A., Mutavci Gh., Ciobanu M., Popa V. Unele aspecte de diagnostic i
tratament chirurgical al sindromului posttromboflebitic la membrele inferioare. Arta Medica,
N4 (25), Chiinu, 2007, p. 18-19.
27. . ., .., .. ,
, 1985, . 554.
28. .. , , 1987, 2.
29. .. , , 1974, 3, .
235-236.

VARIABILITY OF AORTIC ARCH BRANCHING

Abu Husseine Amer
(Scientific Advisor - Assoc. Professor Tamara Hacina)
Department of Human Anatomy
Summary
50 aortic arches were studied in adult cadavers (aged 26-73 years) for variations in the origin
of branches at arch of aorta, the relative distances between the adjacent branches were observed.
Rezumat
Variabilitatea ramificrii arcului aortic
Au fost studiate 50 aorte umane preluate de la persoane mature decedate n vrsta de la 26
pn la 73 de ani. Atenie a fost acordat variabilitii originii ramurilor aortei i distanei ntre
ramuri adiacente.
Novelty of Theme
The aortic arch is a challenging site for endovascular repair. Complication of open surgery of
the AA include ischemic problems which can be caused by unrecognized variation of the
vascular anatomy. The morphologic variations of the AA and its branches are significant for
diagnostic and surgical procedures in the thorax and neck.
Aim
To investigate the prevalence and imaging appearances of anatomical variations of the
common aortic arch, the present work was to study the branching pattern of the aortic arch, the
diameters of its branches and the distance between their origins. This study would provide an
anatomical basis to assist surgeons in performing safe vascular surgery involving the AA, and its
branches in cases in which stenting are used as an adjunct to balloon angioplasty for the
treatment of both stenotic and occlusive lesions of the supra aortic trunks.
81

Materials and methods

This study was performed on 50 adult human preserved mediastinal complexes and 5 predissected separate hearts with the aortic arches en-bloc.
The following morphological parameters have been recorded:
Examination of the branching pattern of the aortic arch major branches.
Identifying additional arteries originating from the aortic arch.
Measuring the distance between the branches originating from the arch.
Measuring the diameter of all branches at the site of their origin from the arch.
Measurements were done using a Vernier caliper, accuracy 0.01 mm.
Additionally, photographs were taken using digital camera (Panasonic VDR-D150).
Discussions and results
The common branching pattern of the AA in which the three major branches originated
independently was observed. In this study the most
common AA branching pattern was found in 85%
of the specimens. In this pattern the three major
branches: brachiocephalic trunk (BT), left
common carotid (LCC), and left subclavian (LS)
Fig. 1.A photograph of the aortic arch (AA)
showing its common branching pattern. The
three major branches arise independently from
the arch.
A ascending aorta; B aortic arch; C
isthmus; D descending thoracic aorta. 1
brachiocephalic trunk; 2 left common carotid
originated
the arch of the aorta (fig.1). According to Lippert and Pabst this
artery; 3 independently
left subclavianfrom
artery.
pattern was in 70%, different from that found by Shin et al. (84%) and Paraskevas et al. who
found it in only 65%.
Tab. 1.The mean diameter of the aortic arch branches
Aortic branch
BT
LCC
LS

The mean diameter

17.87 3.81 mm
9,69 1,90 mm
14.33 3.09 mm

Minimum
11.0 mm
6.1 mm
7.1 mm

Maximum
24.5 mm
14.8 mm
19.8 mm

Tab. 2. The mean distance between the origin of the aortic arch branches
The mean distance between
BT - LCC
LCC- LS

Minimum
0,1 cm
0,3 cm

Maximum
0,5 cm
2.0 cm

The anomalous origins of the branches of the AA is attributed to the altered development of
certain brachial arch arteries during the embryonic period of gestation.
The AA in two specimens of the above group (2%) had only 2 great branches. They
originated from the upper convex surface of the aortic arch. The first was a common trunk,
which incorporated the BT and the LCC. The second was the LS, which arose independently
distal to the origin of the common trunk (fig.2 ).

82

In four cadavers (8%) an additional artery was noted in

addition to the three branches and four branches had their
origin from the upper convex surface of the arch. The
additional branch was traced and found to be left vertebral
artery (LV). It had an independent origin from the aortic
arch. It was located between the origins of the left common
carotid and the left subclavian arteries. The arising
sequence of the four arteries from the arch, from right to
left was BT, LC, LV, and LS (Fig. 2).
In only one cadaver (1%) the LV arose from aortic arch
separated. This branch originated from the arch behind the
LCC, its diameter was 3.0 mm.
One remarkable finding in the present work was the
origin of LV with the LS from a common trunk in one
cadaver (2%) out of nine variations. The trunk originated
from the arch behind the LC. Its diameter was 19.2 mm. Fig.2. A photograph of the aortic
No similar finding was reported in the current literature arch showing its two branches.
1 brachiocephalic trunk fused
review.
Usually described three branches arising at arch of with the left common carotid
aorta were observed in 85% specimens. Two branches artery; 2 left subclavian artery;
arising from arch of aorta, having different branching 3 right subclavian artery; 4
pattern were observed in 2%; four- in 10%; five in 3%. right common carotid artery; 5
The openings of the arteries were oval in shape in 85% left common carotid artery; 6
with the mean maximum anteroposterior diameters being arterial ligament.
greater than the mean maximum side-to-side diameters,
while they were elliptical in 10%. The BC artery showed largest size followed by LSC and then
LCC in most of the branching patterns (p< 0.001). The mean transverse distances between
adjacent lumenal openings of these branches were
significantly greater than the mean vertical
distances (p < 0.001). Approximation of LCC to
BC trunk was seen in 10% specimens. The most
frequent anatomical variant was an additional
branch , which occurred in 20% of cases (Fig. 3).

Fig.3. A photograph of the aortic arch

showing its four branches.
1 right subclavian; 2 - right common
carotid artery; 3 left common carotid
artery; 4- left subclavian artery.

Conclusions
In conclusion, the different branching patterns of the AA observed in this study and the
morphometric measurements taken can assist surgeons in performing safe and effective surgeries
in the superior mediastinum.
With the ever increasing complex endovascular interventions in the aorta and head and neck
regions, recognition and appreciation of these entities is of importance to the interventional and
diagnostic radiologist alike.

83

1.

2.

3.
4.
5.

Bibliography
Bhatia K, Ghabriel MN, Henneberg M. Anatomical variations in the branches the human
aortic arch: a recent study of a South Australian population. Folia Morphol (Warsz) 2005;
64(3): 217-223.
Goray VB, Joshi AR, Garg A, Merchant S, Yadav B, Maheshwari P. Aortic arch variation: a
unique case with anomalous origin of both vertebral arteries as additional branches of the
aortic arch distal to left subclavian artery. AJNR Am J Neuroradiol 2005; 26(1): 93-95.
Lippert H, Pabst R. Aortic arch. In: Arterial Variations in Man: Classification and Frequency.
Munich, Germany: JF Bergmann-Verlag, 1985. 310.
Nayak SR, Pai MM, Prabhu LV, DCosta S, Shetty P. Anatomical organization of aortic arch
variations in the India: embryological basis and review. J Vasc Bras 2006; 5(2): 95-100.
Shin Y, Chung Y, Shin W, Im S, Hwang S, Kim B. A morphometric study on cadaveric aortic
arch and its major branches in 25 Korean adults: the perspective of endovascular surgery. J
Korean Neurosurg Soc 2008; 44(2): 78-83.

VARIATIONS OF THE MANDIBULAR CANAL, MANDIBULAR AND MENTAL

ORIFICES
Simcha Pirov, Aviva Pirov
(Scientific Advisor - Assoc. Professor T. Hacina)
Department of Human Anatomy
Summary
The present study assesses variabilities of mandibular canal, the relative position, size and
shape of its mandibular and mental foramina, evaluates their measurement and relationship with
various landmarks of the mandible in adults. The current study traced out that some of the
mandibles had accessory mandibular and mental foramina.
Rezumat
Variabilitatea canalului mandibular, orificiului mandibular i mental
Studiul de fa elucideaz variabilitatea canalului mandibular, poziia relativ a orificiilor lui
mandibular i mental, evalueaz datele de morfometria a acestora i demonstreaz raporturile lor
cu diverse puncte de reper ale mandibulei la aduli. n acest studiu au fost constatat prezena
orificiilor supranumerare.
News Theme
Knowledge of mandibular and mental foramina location is useful for the oral and
maxillofacial surgeon in orthognatic surgery, especially in vertical ramus osteotomy procedure,
in local anesthesia making. The development of implant techniques increased the interest in the
mandible anatomy, specially the mandibular foramen localization. Despite this interest a small
number of papers has been published on the position of mental foramen. The knowledge of the
additional foramina may be important for the radiotherapists while planning radiation therapy.
This knowledge is also important for orthognathic or reconstructive surgeries of the mandible
and dental implant procedures.
Aim
The aim of this study is to describe morphological variability of mandibular canal and to
analyse the position, shape and size of the mandibular and mental foramina in order to provide
simple and reliable surgical landmarks.

84

Materials and methods

The study of location, shape and size of the mandibular and mental foramina was performed
on directly measures and observations on 37 dry human mandibles which were selected from the
skeletal collection of the Department of Anatomy of our university and 30 radiographs taken
from Department of Stomatology. All were adult mandibles, the exact ages of which were
unknown. The measurements were performed with a digital pachymeter of 0.01 mm accuracy.
Images of the mandibles were obtained using a digital camera.
Discussions and results
The mandibular canal is a canal within the mandible that contains the inferior alveolar
nerve, inferior alveolar artery, and inferior alveolar vein. It runs obliquely downward and
forward in the ramus, and then horizontally forward in the body, where it is placed under
the alveoli and communicates with them by small openings. On arriving at the incisor teeth, it
turns back to communicate with the mental foramen, giving off a small canal known as
the mandibular incisive canal, which run to the cavities containing the incisor teeth.[1] The
location and configuration of mandibular canal variations are important in surgical procedures
involving the mandible, such as extraction of an impacted third molar, dental implant treatment,
and sagittal split ramus osteotomy (Naitoh m et al., 2007). The mandibular canal is fairly close to
the apices of the second molar in 40% of the radiographs. In 50%, canal is away from the root
apices, and in only 10% of the radiographs the root apices appeared to penetrate the canal.
In root canal therapy of the second molar one should be cautious of over extending the reamer
or the root canal filling materials because there is a possible risk of inferior alveolar nerve injury.
It was reported that in 60% of the cases, the mandibular canal was found to have the entire
inferior alveolar nerve passing through it, while in the remaining 40% cases, the nerves were
found to be scattered. This observation of the spread of the inferior alveolar nerve suspects the
possible presence of some other nerves which pass through the mandibular canal, probably the
nerves to the mylohyoid.
In the present investigation position of mandibular and mental foramina in relation to other
landmarks were studied. The prevalence rate and the laterality were analyzed. The
morphological knowledge of the MF is of paramount importance during the dental procedures of
the lower jaw, as structures that go through this foramen should be preserved.
The mandibular foramen (MF) is a prominent feature on the medial surface of the ramus of
the mandible which is located just above its centre. This foramen is at approximately the
midpoint of the internal surface of the ramus. It is the opening into the mandibular canal. It
provides passage to the inferior alveolar branch of the mandibular nerve and its accompanying
vessels. This study assessed the mandibular foramen (MF) position variability in dentate and
edentate mandibles. 23 dentate and 14 edentate mandibles of unknown sex were measured
bilaterally using a digital caliper (0.1-mm precision).
Horizontal linear measurements were done from the MF to the anterior border of the
mandibular ramus and from the MF to the posterior border of the mandibular ramus. Vertical
linear measurements (VM) were done from the MF to the most inferior point of the mandibular
notch (MF-N) and from the MF to the inferior border of the mandibular ramus (MF-D).
Tab.1.The results obtained in the study of MF position
Mean distance between
MF- anterior border of the mandibular branch
MF- posterior border of the mandibular branch
MF- center of mandibular branch
MF- lowest point of mandibular notch
MF- inferior border of the mandibular branch
Narrowest anteroposterior diameter of the branch
85

Right side
16,72 mm
14,21 mm
Posteriorly 0,54 mm
22,41 mm
30,56 mm
32,8

Left side
16,78 mm
14,41 mm
Posteriorly 0,63 mm
22,23 mm
29,83 mm
32,05

Dentate mandible measurements showed statistically significant differences compared to the

edentate mandibles, except for MF-N. The mandibular foramen position changes with loss of
teeth and this variability may be responsible for occasional failure of inferior alveolar nerve
block (tab.1).
The mandibles were observed for the presence of AMF and if they were present, a further
observation was made about their numbers. Their prevalence rate and laterality were also
analyzed. A magnifying lens was used for the observations.There are a few cases which have
been reported on the accessory mandibular foramina (AMF) and the incidence of the AMF has
been found to be greater on the medial surface than on the lateral surface [3-5]. The branches of
the facial, mylohyoid, buccal and the transverse cervical cutaneous nerves are known to pass
through these accessory foramina. It has been described that the presence of an AMF in the
mandible also indicates that extra blood vessels traverse it, which supply the bone.
The current study observed that some of the
mandibles had accessory foramina (two or three
mandibular foramina). These foramina are clinically
important as they can lead to diagnostic and
therapeutic misinterpretations. The operating surgeons
should be aware of these foramina and they should
plan the anaesthesia at an appropriate site. During
surgical procedures which involve the ramus of the
mandible, it is important to be familiar with the
incidence and the configuration of these foramina,
since complications including unexpected bleeding,
paraesthaesia and traumatic neuroma are known to
occur because of trauma to the accessory canal. The
Fig. 1. Photograph of the lateral
morphological knowledge of these foramina is
surface of the right half of the
important as they transmit the branches of the nerves
mandible showing a single accessory
which supply the roots of the teeth. The local
mental foramen.
anaesthetic drug which is given in this region may
fail if these nerves or their branches pass through the accessory foramina.
From our observations, it was found that the accessory mandibular foramen was present in
12.3% of the mandibles. It was present unilaterally in 8.9% of mandibles (3 on the right side and
3 on the left side) and bilaterally in 7.5% cases. The gender wise frequency was recorded as 6:5
in the male and female mandibles. The accessory foramen was single in 9 cases and double in 2
cases. In all the cases, the accessory foramen was directed downwards towards the alveolar
margin.
A large accessory mandibular foramen (AMF) was present postero-superior to the normal MF
(left side) in 1 of mandibles observed. The diameters of this foramen were 10 mm anteroposteriorly and 5 mm vertically, and that of MF were 7 mm antero-posteriorly and 5 mm
vertically. The distance between these 2 foramina was 11 mm, and between the AMF and the
apex of the lingula was 4 mm. The distances from the posterior limit of AMF to the posterior
border of the ramus and angle were 18 mm and 52 mm, respectively.
The position of the mandibular foramen was found to be variable. However, the foramen was
predominantly located at the anteroposterior midpoint of the ramus halfway between the
mandibular notch and the lower surface of the mandible and two thirds of the way down a line
joining the coronoid process to the angle of the mandible. In the majority of the mandibles
studied the foramen was located below the occlusal surfaces of the molar teeth.
The mental foramen (MeF) is a structure, through which the inferior alveolar nerve and blood
vessels pass together to the buccal gingiva in front of the second premolars to the lower lip and
chin. The orientation and position of the mental foramen was visually inspected. According to its
orientation it was classified as posterior-superior, superior and posterior. The posterior-superior
direction is the most common orientation of exit of the mental foramen.
86

In order to determine the position of the mental foramen in relation to the anterior and
posterior borders of the mandible a horizontal line was drawn from the most proeminent point of
the mandible symphysis to the posterior border of the ramus of the mandible. The following
distances were measured (tab.4):
1) from the most proeminent point of the mandibular symphysis to the anterior border of the
MeF;
2) from the posterior border of the MeF to the posterior border of the mandible;
3) from the inferior border of the mandible to the inferior border of the MeF.
There was no significant variation of the shape of the MF. The mental foramen may be round
or oval (60,15%) in shape, it may be absent, unilateral or bilateral and in some cases may be
multiple on one or both sides of the mandible. Its diameter is 3-7 mm.
Comparison of the study results with the other studies
Table 2 - Position of the mental foramen
Prabodha et al.
Study results
Mean distance from
Mandibular symphysis
26.52 mm
27,14 mm
Posterior border of the ramus of the mandible
65.38 mm
64,72 mm
Inferior border of the body of the mandible
12.25 mm
13,83 mm
Table 3 - Shape of the mental foramen
Shape
Mbajiorgu et al.
Gershenson et al.
Oval
56.3%
65.52%
Round
43.8%
34.48%

Prabodha et al.
66.67%
33.33%

Study results
60,15%
39,85%

In an adult with the advancement of the age MF was moved towards the superior border of
the body of the mandible (fig. .). This is mainly because of the loss of teeth and alveolar bone
resorption. There is a significant variation of the position of the MF with age. This is also
compatible with Prabodha et al. study.
Simple percentage evaluation was used to determine the frequency of the mental foramen in
relation to the lower teeth. In 50% of cases it is located at the adge of the second premolar root,
in 25% it is between the first and second premolars and 25% it is behind the second premolar.
It is important to report on the risk of anatomical variation of mental foramina, in order to
avoid nerve damage in connection with surgical procedures. The absence and variation of
accessory mental foramina has been reported in dry
human mandibles and on radiographs previously, and
can range from (0.2%) to (10.6%) on one side. A
double mental foramen in our study appears in
approximately 1% on the left side and in 1.1% on the
right side of the mandible .
Gershenson et al. (1986) who examined 525 dry
mandibles focusing on variation, shape and site
of the mental foramen related to the teeth, reported
that 4.3% mandibles had double mental foramina, and
0.7% mandibles had triple mental foramina. Finally
they found one mandible that had four mental foramina
on one side (0.1%).
Katakami et el. (2008) examined 150 patients Fig. 2. Photograph of the anterior
retrospectively with limited cone-beam computed surface of the mandible two
tomography and depicted 16 double foramina (10.6%) accessory mental foramina on the
right side.
and triple mental foramina on one side (0.6%).
87

The location of the mental foramen in relation to the mandibular teeth was assessed in the
dentate mandible. The location of the mental foramen is an important factor when considering
the mental and incisive anesthetic block and surgeries in the outer premolar mandibular region.
The present study shows the location in line with the long axes of the second premolar as the
most common position of the mental foramen, followed by the position between the first
premolars. In the present study this parameter is not influenced by gender.
Mental foramen was often observed in the apical of second premolar, while the accessory
mental foramen was detected between apical of second premolar and first molar or between
apical of canine and lateral incisor.
In most cases mental foramen of adult dentate mandible is located halfway between the
lower border of mandible and alveolary crest in a vertical line with the supraorbital notch.
The retromolar foramen (RMF) was found to occur in forth of 37 adult human mandibles
studied (10.7%). No statistically significant difference was found between left and right sides or
between sexes.
Additional foramina are clinically important as they can lead to diagnostic and therapeutic
misinterpretations.
Conclusions
1) The location and configuration of the mandibular canal is variable and should be carefully
observed using cross-sectional images of the mandibular canal and images perpendicular to
them when conducting surgical procedures such as implant treatment involving the mandible.
2) A number of studies have shown: a) variability of distance between the MF and mandibular
notch; b) difference in the position of the mental foramen in relation to the second premolar
and to the alveolary crest; c) the presence of additional mandibular, mental and retromollar
foramina.
References
1. Agthong S, Huanmanop T, Chentanez V. Anatomical variation of the supraorbital,
infraorbital, and mental foramina related to gender and side. J Oral Maxillofac Surg 2005;
63:800-4.
2. Ajit Auluck, Ausaf Ahsan, Keerthilatha M. Pai, Chandrakant Shetty. Anatomical variations
in developing mandibular nerve canal: a report of three cases. Neuroanatomy (2005) 4: 28
30.
3. Anwar Ramadhan, Elias Messo, Jan-Michal Hirsch Anatomical Variation of Mental
Foramen. A case report. Stomatologija, Baltic Dental and maxillofacial Journal, 12: 93-6,
2010.
4. Ayla Ozturk, Anitha Potluri, Alexandre R. Vieira. Position and course of the mandibular
canal in skulls. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Volume
113, Issue 4, April 2012, Pages 453458.
5. Greenstein G, Tarnow D. The mental foramen and nerve: clinical and anatomical factors
related to dental implant placement: a literature review. J Periodontol. 2006;77:1933 43.
6. Hasan Tabinda, Fauzi Mahmood, Hasan Deeba. Bilateral absence of mental foramen a
rare variation. International Journal of Anatomical Variations (2010) 3: 167169.
7. Igarashi C, Kobayashi K, Yamamoto A, Morita Y, Tanaka M. Double mental foramina of
the mandible on computed tomography images: a case report. Oral Radiol. 2004;20:68 71.
8. Phillips JL, Weller RN, Kulild JC. The mental foramen: 3size and position on panoramic
radiographs. J Endod 1992;18:383 6.
9. Sawyer DR, Kiely ML, Pyle MA. The frequency of accessory mental foramina in four
ethnic groups. Arch Oral Biol 1998;43:41720.
10. Marzola Clvis et al. Mandibular foramen contribution to your localization to the
anesthetical techniques. Revista ATO, 2004: 652 -678.
11. Miloglu Ozkan, Ahmet Berhan Yilmaz, Fatma Caglayan. Bilateral bifid mandibular canal:
88

A case report . Med Oral Patol Oral Cir Bucal. 2009 May 1;14 (5):E244-6.
12. Naitoh M, Hiraiwa Y, Aimiya H, Gotoh K, Ariji E. Accessory mental foramen assessment
using cone-beam computed tomography. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2009;107:289-94.
13. Naitoh M, Hiraiwa Y, Aimiya H, Gotoh M, Ariji Y, Izumi M, et al. Bifid mandibular canal
in Japanese. Implant Dent. 2007;16:24-32.
14. Nortj C.J., Farman A.G., Grotepass F.W. Variations in the normal anatomy of the
inferior dental (mandibular) canal: A retrospective study of panoramic radiographs from
3612 routine dental patients. British Journal of Oral Surgery, 1977, Volume 15, Issue 1 ,
Pages 55-63.

MORPHOLOGICAL VARIABILITIES OF THE SKULL

Aviva Pirov, Simcha Pirov
(Scientific Advisor - Assoc. Professor T. Hacina)
Department of Human Anatomy
Summary
The article describes different aspects of variability of the human skull: gender, age and
ethnic. An attempt of systematization of the structural features of the skulls is undertaken .
Rezumat
Variantele morfologice ale craniului
n articol se descriu diferite aspecte referitoare la variabilitatea craniului uman: de sex, de
vrst i apartenena etnic. Este ntreprins ncercarea sistimatizrii particularitilor structurale
ale craniilor.
News Theme
One of the most important aspects of behavior management in pediatric dentistry is pain
control. Basically, in order to have a rapid, deep and safe local anesthesia, location of MF in
relation to the occlusal plane should be acquired. As the child grows up, the position of MF
changes. Hence, for a successful mandibular local anesthesia, consideration to such changes is
imperative. Differences between male and female skull and between individuals of different
races are very important in forensics to determine the sex of the skull which has been recovered
and in the establishment of a victims ethnic origin.
Aim
The aim of this study is to investigate the influence of age and gender on the structure of the
human skull. The purpose of this investigation was to establish how the mandibular angle
changes with age and loss of teeth among the sexes.
Materials and methods
A wide range of literature on the subject was studied, and made an observations were made
on 30 human skulls which were selected from the skeletal collection of the Department of
Anatomy of our university, College of Medicine and 20 radiographs taken from the Department
of Stomatology. Ten of them were child and twenty adult skulls. Images of the skulls were
obtained using a digital camera.
Discussions and results
The skull is the bony section of the head. The skull encases and protects the brain, houses the
brain senses, provides attachments for muscles of the head and neck, and helps to form the first
89

portions of the respiratory and digestive tracts. At birth, the skull is large in comparison to the
rest of the body, and a baby's skull is compressible. A human skull is almost full sized at birth.
However the 8 bones that make up the cranium are not yet fused together. This means that the
skull can flex and deform during birth, making it easier to deliver a baby through the narrow
birth canal. The "soft spots" in a baby's head harden and grow together until the bones meet and
mesh like a jigsaw puzzle. The largest of the six main soft spots is a diamond-shaped area near
the middle of the top of the skull. This is the last area to harden and close, usually at about the
age of eighteen months.
The skull of the infant is markedly different from that of the adult. At birth the face is quite
small and undeveloped, while the cranium is relatively large. The frontal and parietal eminences
are very marked. The vault of the skull is not entirely ossified and the sutures are not completed.
The bones of the base of the skull originate in cartilage, while those of the vault originate in
membrane. This membrane has one or more centres of ossification appearing in it for each bone.
These centres increase in size and finally meet at the edges of the bone, thus forming the sutures.
At the time of birth the sutures are represented by membrane, which joins the adjacent bony
edges. The frontal bone has two centres of ossification; one for each side. These form a suture in
the median line of the forehead which becomes obliterated in the course of the first or second
year. Traces of it in the shape of a groove or ridge can sometimes be seen or felt in the adult
skull.
The frontal eminences are far more marked in childhood than
later in life and give to children the prominent forehead. A similar
peculiarity is seen in the parietal bones, the parietal eminences
being quite prominent. On this account, they are often injured in
childbirth, sometimes being compressed by the obstetrical forceps,
and are frequently the seat of haematoma neonatorum. The cranial
bones not being firmly united allow of a certain amount of play or
even overlapping, thus facilitating the delivery of the head at birth.
At the juncture of the various bones there are six spaces called Fig. 1. The body of
fontanelles. Two, the anterior and posterior, are in the median line the mandible with
of the cranium, and four, the two anterolateral and two completely resorbed
posterolateral, are at the sides. The fontanelles are situated at the alveolary process.
four corners of the parietal bones.
The anterior fontanelle is the largest. It is diamond-shaped and formed by the frontal suture in
front, the interparietal behind, and the coronal at each side. It is usually closed by the end of the
second year, but may be delayed until the fourth. In rickets and malnutrition the fontanelles
remain open longer than would otherwise be the case.
The posterior fontanelle is formed by the juncture of
the parietal (sagittal) suture with the lambdoidal suture.
It is triangular in shape with the apex forward between
the two parietal bones, the sides passing down, one to
the right and the other to the left of the top of the
occipital bone.
The pliable head which allowed the child to safely
pass through the birth canal is also responsible for
enabling normal human development during the first 18
months of a child's life. During this period the brain
grows rapidly and the skull has to be flexible enough to
adapt to its growth. The natural development of the
Fig. 2. Mandible of the infant (A)
cranial and facial bones involves changes in skull shape,
and adult (B).
which is also accommodated by the lack of a
permanently fused skull. The permanent skull is fused between the ages of 20 months and two
years.
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During an individual's life, the morphological changes undergone by the mandible are thought
to be influenced by the dental states and age of patient.
The mandible and also the associated maxillary alveolar process may be almost completely
resorbed in elderly edentulous patients (Fig.1).
Tab.1. How to know roughly the age of the mandible?
Age
At birth
At 4 years
Adult

Old age

Angle
About 170
(very obtuse)
About 145
(25 less)
About 120
(25 less)
About 145
like young age again

Mental foramen
Near the lower border

Alveolar border
No eruption of the teeth

Slightly higher in
position
Midway between the
upper and lower
borders
Near the upper border
(due to absorbtion of
the alveolar margin)

Eruption of the 10 milk

teeth
Eruption of the 16
permanent teeth
Shows loss of teeth and
absorbtion of the
alveolar margin

The funnel-shaped lip of the mandible in old age causes the prominent chin and leads to a
reduced height of the lower face. In old age, the mandible is shaped like a clasp and flattened so
that it looks similar to the mandible of a newborn.
Severe atrophy results in the mental foramen becoming relatively more superior and closer to
the upper edge of this clasp and no longer visible from the vestibule. Atrophy of the alveolar
process significantly reduces the distance from the mandibular canal to the upper edge of the
mandible so that in rare cases the inferior alveolar nerve is located directly underneath the
mucosa.
Male and female skulls also show
significant differences in structure (Fig.3). The
small bulge at the back of the head known as
the external occipital protuberance is usually
more pronounced in men. The male jawbone
or mandible is typically angular and squareshaped at the chin area, while the female
jawbone tends to be more rounded and
pointed. The brow ridges of men are often
more prominent than those of women. These
distinctions in cranial and facial features
underlie the basic difference between men's
and women's faces.
All dimensions of the female skull and
face are smaller compared to the male
features. The facial width is relatively larger in
women than in men. Resulting contours are
therefore more rounded in females, especially
in the orbital area, with more prominent malar
(cheek) bones and less prominent mandibular
(chin/jaw) angles.
Fig. 3. Sex differences of the skull.
In the upper part of the face, the forehead is
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quite different, most noticeably women have less sloping mid-foreheads and the position of their
eyebrows is higher and has a stronger curvature.
In the middle part of the face, the angles of the nose differ substantially, especially at the tip
portion. Females generally have a more pointed, narrow, and vertically shortened less nasal
prominence than males.
Tab.2. Sex and gender differences of the skull
Cranium Feature
General size
Architecture
Supraorbital torus
Mastoid process
Occipital bone
Frontal eminence
Parietal eminence
Orbit

Forehead
Cheek bones
Mandible

Ramus of mandible
Symphysis and mental
eminence of mandible
Palate
Occipital condyles
Posterior part

Frontal Bone
Temporal Ridge
Bony superciliary arches
Mastoid process
Supraorbital margin
External occipital
protuberance
Nuchal crest
Nuchal line
Zygomatic process (cheek
bones)
Paranasal sinuses
Teeth
Cranium
Total skull

Male
Large
Rugged
Medium to large
Medium to large
Muscle lines and protuberance
marked
Small
Small
Squared, lower, relatively
smaller with rounded superior
margins
Steeper, less rounded
Heavier, more laterally arched
Larger and more robust, higher
symphysis, gonial angle less
then 125, gonial angle flares
and is sharply angled
Straight
Square

Female
Small
Smooth and gracile
Small to medium
Small to medium
Muscle lines are not marked
Large
Large
Rounded, higher, larger with
very sharp superior margins
Rounded and full, sometimes
infantile
Lighter, more compressed
Smaller and lighter, gonial
angle more then 125, gonial
angle does not flare as much
outward and sharply angled
Slanting
Rounded (generally) or pointed

Larger, broader, tends to the Ushaped

Large
Has a protuberal crest that may
continue posteriorly to meet
with the most inferior curve on
the temporal lines
Lower/sloping
Large
Prominent
Large
Rounded
Generally present

Small, tends to be a parabola

Rugged, well defined

Rugged and sharp
Extends past external auditory
meatus
Larger
Larger
Deeper and larger by about 10%
Rougher, heavier

Smoother, even absent

Absent
Does not extend past
(generally)
Smaller
Smaller
Smaller
Smoother and more rounded

92

Small
Crest usually not as
pronounced, does not continue
across to temporal lines
More vertical and rounded
Small
Absent/slight
Small (generally)
Sharp
Generally absent

In the lower part of the face the most dominant differences are found in the chin region, which
varies markedly between the male and female. The male chin is larger in every dimension, the
mandible symphysis (upper chin) is generally wide and vertically high, while the female is more
rounded, and the male mental eminence (point of the chin) tends to be square and the female
more pointed. The degree of perceived masculinity/femininity due to the chin can vary
tremendously.
Bishara et al. (1990) showed that dento-facial parameters are bound to ethnic origins.
Until the age of puberty there is little difference between the skull of the female and that of
the male. The skull of an adult female is, as a rule, lighter and smaller, and its cranial capacity
about 10 per cent. less than that of the male. Its walls are thinner and its muscular ridges less
strongly marked; the glabella, superciliary arches, and mastoid processes are less prominent, and
the corresponding air sinuses are small or rudimentary. The upper margin of the orbit is sharp,
the forehead vertical, the frontal and parietal eminences prominent, and the vault somewhat
flattened. The contour of the face is more rounded, the facial bones are smoother, and the
maxill and mandible and their contained teeth smaller. From what has been said it will be seen
that more of the infantile characteristics are retained in the skull of the adult female than in that
of the adult male. A well-marked male or female skull can easily be recognized as such, but in
some cases the respective characteristics are so indistinct that the determination of the sex may
be difficult or impossible.
We have found that there are the key skull differences between the female skull and the male
skull. First of all, the male cranial mass is more blocky and massive compared to the females
one which is more rounder and tapers at the top.
Secondly, the females brow ridge margin is sharper while the males one is rather rounded
and dull. Thirdly, the zygomatic bone is more pronounced on the male skull than on the female
skull.
The Mandible or the lower jaw is more rounded on the female skull while the male skull is
squared. Also, the male have a deeper cranial mass than the female dose. And, last but not leastthe superciliary arch of the male skull is more pronounced and larger than the female skull.
There is a number of differences in the structure and appearance of bones between individuals
of different races that can be observed and used in the establishment of a victims ethnic origin.
The majority of these differences are based in the skull.
Caucasian skull, or white European descended people have relatively no prognathism (or the
extension of the lower jaw) and relatively little projection of the alveolar ridge. Faces are
typically smaller, with a tear-shaped nasal cavity and tower-shaped nasal bones. The palate is
triangular and the skull has a sloping eye orbital formation. The forehead and cranium are
prominent.
Mongoloid skull, or Asian people have small to no extension of the lower jaw and the nasal
sill or dam, and an oval nasal cavity. The nasal bones are tent-shaped and the palate is horseshoeshaped. The eye orbital is rounded and non sloping, and the cranium is generally rounded.
Black, or Negroid skulls feature a broad and round nasal cavity and no dam or nasal sill.
There is notable facial projection in the jaw and mouth area and a rectangular palate. The eye
orbit shape is square or rectangular. The skull is dolichocephalic, which means longer from front
to back proportionally.
In general, the racial group to which the person belongs is determined by examining the width
and height of the nose. It is important to note that many of these characteristics only have a
higher frequency among particular races and the presence or absence of one or more does not
automatically classify an individual into a racial group. Different human populations have
developed close proximity to one another due to mixed ethnic heritage.

93

Nasal Cavity

Prognathism

Eye Orbit

Mouth and
teeth

Zygomatic
bones

Tab.3. Differences in the structure and appearance of bones

between individuals of different races
Caucasian/European Negroid
Mongoloid
Steep towering nasals Semicircle nasals
Tented nasals but not towering
Large nasal spine
Small nasal spine
and sharp. Diamond shaped
Narrow nasal aperture Large nasal aperture node holes
Triangular nose holes Square nose holes
Small nasal spine
Nasal aperture larger than
Caucasian
Maxillary
Mandibular
Most often no prognathism,
prognathism
prognathism
face relatively flat.
"overbite"
"underbite"
Chin is more vertical. If
prognathism is present it
favors a maxillary trend
Angular,
Square or
Round,
lower eye border
rectangular,
lower eye border projecting
receding
lower eye border
receding
Parabolic dental arch
Hyperbolic
Dental arch is rounded,
and spatulate teeth
rectangular-shaped
incisors shoveled swollen
shaped like a spatula;
palate and
lateral borders and a hollow in
rounded more or less
megadontic teeth,
the center of the crown
like a spoon.
spatulate
Curved
Curved
Squared

Conclusions
Knowledge of the large variability of the human skull is needed to dentists, pediatricians,
specialists of forensic services for the proper implementation of the anesthesia and plastic surgery,
assessment of child development, and for the establishment of a victims origin.
Bibliography
1. Fabian F.M., Mpembeni R. Sexual dimorphism in the mandibles of a homogenius black
population of Tanzania Tanz. J. Sci. Vol. 28(2) 2002: 47-54
2. Gldner C, Zimmermann AP, Diogo I, Werner JA, Teymoortash A.. Age-dependent
differences of the anterior skull base. Int J Pediatr Otorhinolaryngol. 2012 Jun;76(6):822-8.
Epub 2012 Mar 23.
3. Gwilym G. Davis. "Applied Anatomy: The Construction Of The Human Body", 1913.
4. Krzypow A.B., Orth D., Lieberman M.A., Michaela Modan, M.Sc.. Tooth, face,
and skull dimensions in different ethnic groups in Israel American Journal of Orthodontics,
1974, Volume 65, Issue 3, Pages 246249
5. Luiz Airton Saavedra de Paiva and Marco Segre Sexing the human skull through the mastoid
process. Rev. Hosp. Clin. Fac. Med. , 2003, S. Paulo, 58(1):15-20.
6. Rushton J. Philippe Sex and race differences in cranial capacity from international labour
office data. Intelligence, Volume 19, Issue 3, 1994, Pages 28129.
7. Susanne Gh., Assunta Gwidetti, Houspie R.. Age changes of skull dimensions. Anthrop. Anz.,
Stuttgart, 1985, Jg. 43, 1, 31-36.

94

VARIABILITY OF THE LEFT ATRIOVENTRICULAR AND SEMILUNAR VALVES

Roman Harmelin, Anton Zilbert
(Scientific advisor - Assoc. Professor T. Hacina)
Department of Human Anatomy
Summary
The study was performed in order to determine possible variations of the mitral and aortic
semilunar valves and their frequency.
Rezumat
Variabilitatea valvei atrioventriculare stngi i semilunare aortice
Rezultatele cercetrii demonstreaz variante posibile ale valvei mitrale i celei semilunare
aortice i frecvena lor.
Aim
In order to improve our understanding of left part of the heart, we studied mitral valves and
aortic valves; the aim of this study was directly to describe morphological variability of mitral
and aortic valves.
Materials and methods
For research of, form, sizes of valves, location of coronary openings and number of papillary
muscles with chordae tendineaes in the left part of heart, we measured and supervised 20 hearts
which were selected randomery from the collection of Anatomy Department of the university.
All studied hearts had a different age (exact ages were unknown). Measurements were executed
by a ruler, images of a structure of the left part of heart were made, by using digital camera.
Discussions and results
The two semilunar valves, aortic and pulmonic, guard the outlet orifice of their respective left
and right ventricles. The two AV valves, mitral and tricuspid, guard the inlet orifice of their
respective left and right ventricles.
The atrioventricular valves are, therefore, intricate and complicated structures, having several
components. Each of these components must function correctly and in a coordinated fashion if
the valve itself is to be competent.
The left ventricle is described in terms of three parts : an inlet, containing an atrioventricular
(mitral) valve and its tension apparatus; a trabecular body; and an outlet supporting an arterial
(aortic semilunar) valve.
Mitral valve
The left AV valve or mitral valve (also known as the
bicuspid valve or left atrioventricular valve) is a dual-flap
valve in the heart that lies between the left atrium (LA)
and the left ventricle (LV). The mitral valve is typically
46 cm in area. It has two cusps, or leaflets, (the anterior
(anteromedial or septal) leaflet and the posterolateral or
mural leaflet) that guard the opening (Fig.1). The leaflets
are separated by the posteromadial and anterolateral
commissures. The orientation of the two leaflets
resembles a bishop's mitre, hence the valve receives its
name.
Fig.1. Mitral valve viewed from
The anterior leaflet is attached to less than half the above showing the anterior and the
circumference of the mitral annulus but has considerable posterior leaflet with its three
height and consequently presents as a large leaflet. It is scallops.
the larger and more mobile of the two mitral leaflets,
95

extends from the top of the posteromedial septum across the ventricular cavity to the
anterolateral ventricular wall and separates the left ventricular cavity into an inflow and an
outflow tract.
The funnel-shaped inflow tract, which is formed by the mitral annulus and by both mitral
leaflets and their chordae tendineae, directs the entering atrial blood inferiorly, anteriorly, and to
the left.
The outflow tract, surrounded by the inferior surface of the anteromedial mitral leaflet, the
ventricular septum, and the left ventricular free wall, orients the blood flow from left ventricular
apex to the right and superiorly at an angle of 90 to the inflow tract.
With the onset of ventricular systole, both mitral leaflets are propelled together and upward,
converting the entire left ventricle into an expulsion chamber. The apical portion of the left
ventricle is characterized by fine trabeculations.
The anterior cusp protects approximately two-thirds of the valve. Note that although the
anterior leaflet takes up a larger part of the ring and rises higher, the posterior leaflet has a larger
surface area. These valve leaflets are prevented from prolapsing into the left atrium by the action
of tendons attached to the posterior surface of the valve, chordae tendineae.
Chordae Tendineae
Strong cords of fibrous tissue, the chordae tendineae, spring from the tip of each papillary
muscle. They often subdivide and interconnect before they attach to the two leaflets directly
above. The chordae may attach directly into a fibrous band running along the free edge of the
valves or they may become incorporated into the ventricular surface of the leaflet a few
millimeters back from the edge. Additional chordae run directly from the ventricular wall into
the undersurface of the posterolateral leaflet of the left ventricle.
The chordae tendineae, by their attachments to most of the free valvular border and by their
numerous cross connections, allow the valve leaflets to balloon upward and against each other
and evenly distribute the forces of ventricular systole. Dysfunction or rupture of a papillary
muscle or rupture of a chorda tendinea may undermine the support of one or more valve leaflets,
producing regurgitation.
The posterior leaflet, in contrast, is attached to more than half the circumference but is less
tall , and occupies only about the same area as the anterior leaflet. Moreover, the posterior leaflet
has a characteristic scalloped contour. In the usual case three scallops can be distinguished
divided by clefts. These scallops are termed posteromedial, middle and anterolateral.
The large the variation in the number of scallops exists. In 15% of cases 4-6 scallops being
seen in otherwise normal valves were found, in 3% two scallops only.
The mitral valve leaflets are supported by two
papillary muscles situated underneath the
commissural areas in the posteromedial and
anterolateral positions. Their position is such that
the chordae between muscle and leaflet operate at
the maximal mechanical efficiency. Each
papillary muscle supports the adjacent part of both
valve leaflets.
Papillary muscles
The papillary muscles are located below the
commissures of the AV valves. These muscles
project from the trabeculae carneae. In the left
ventricle the two groups of papillary muscles,
located below the anterolateral and posteromedial
commissures, arise from the junction of the apical
Fig.2. Fan-like papillary muscles.
and middle third of the ventricular wall. The

96

papillary muscles, because of their relatively parallel alignment to the ventricular wall and their
chordal attachments to two adjacent valve leaflets, pull the leaflets of the valve together and
downward at the onset of isovolumic ventricular contraction.
There is considerable variation in the morphology of the papillary muscles themselves,
particularly the posteromedial muscle (Fig.2). They may be single pillar-like muscles, bifid or be
composed of several heads of different size (fan-like papillary muscles). The different papillary
muscle architecture affects the chordal distribution (vide infra) and also affects the mode of the
arterial supply to the papillary muscle complex. Because of the different topography of the
anterior and the posterior leaflets, there are corresponding differences in the mode of chordal
support, which also show considerable individual variation.
The anterior leaflet is supported only by rough zone chordae together with the commissural
chords. The rough zone chords may be strengthened by thicker tendinous structures, the socalled strut chordae, usually one for each half of the leaflet. The commissural chords spring from
the tips of their papillary muscle and fan out to attach to the free margins of both leaflets. The
posteromedial commissural chord usually fans out more than that of the anterolateral
commissure.
As with the aortic valve, mitral valve closes some distance away from its free edge.
The inelastic chordae tendineae are attached at one end to the papillary muscles and the other
to the valve cusps. Papillary muscles are fingerlike projections from the wall of the left ventricle.
Chordae tendineae from each muscle are attached to both leaflets of the mitral valve. Thus, when
the left ventricle contracts, the intraventricular pressure forces the valve to close, while the
tendons keep the leaflets coapting together and prevent the valve from opening in the wrong
direction (thus preventing blood to flow back to the left atrium). Each chord has a different
thickness. The thinnest ones are attached to the free leaflet margin, whereas thickest ones are
attached quite away from the free margin. This disposition has important effects on systolic
stress distribution physiology.
The major chordae supporting a leaflet insert either into its free edge, or the area beyond the
free edge on the ventricular aspect up to the line of closure of the leaflet. This area between the
free edge and the line of closure is termed the rough zone in contradistinction to the area between
the line of closure and the basal attachment of the leaflet which is easily transilluminated and is
smooth. It is important to remember that the line of closure of a leaflet is not its free edge.
The major chordae supporting a leaflet insert either into its free edge, or the area beyond the
free edge on the ventricular aspect up to the line of closure of the leaflet. This area between the
free edge and the line of closure is termed the rough zone.
The chordae inserted into the rough zone are called rough zone chordae. They are
distinguished from basal chordae which pass from the ventricular myocardium to the ventricular
aspect of the leaflet close to its attachment and commissural chordae which are the discrete fanshaped chordae inserting into the free margin of the leaflet only and supporting two adjacent
leaflets.
Abnormalities of the mitral valve:
- Mitral Valve Prolapse: is when one or both valve flaps are enlarged. As a result, when the
heart pumps, the mitral valve flaps don't close smoothly and may not seal tightly. Instead, they
may collapse backward into the left atrium. This sometimes causes regurgitation.
- Mitral Valve Regurgitation: is when the mitral valve does not close well and blood leaks back
into the left atrium from the left ventricle. This causes the atrium to get bigger. Then it cannot
squeeze as effectively as it should.
- Mitral Valve Stenosis: is when the valve becomes narrow or tight. This makes it hard for the
blood to get through to the left ventricle. As a result, blood can back up in the blood vessels of
the lungs. Stenosis can also cause regurgitation.
The aortic semilunar valve is one of the valves of the heart. It is normally tricuspid (with
three leaflets), (in 1% of the population it is found to be congenitally bicuspid) . It lies between
the left ventricle and the aorta.
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The semilunar aortic and pulmonary valves are similar in configuration, except the aortic
cusps are slightly thicker. Each valve is composed of the three fibrous cusps.
The U-shaped convex lower edges of each cusp are attached to and suspended from the root
of the aorta or pulmonary artery, with the upper free valve edges projecting into the lumen. The
cusps circle the inside of the vessel root.
Aortic semilunar valve consists of three equal-sized or nearly equal-sized semicircular cusps.
Each cusp is attached by its semicircular border to the wall of the aorta. The small space between
attachments of adjacent cusps is called a commissure. The semilunar valve has three
commissures. The three commissures lie equally spaced around the aorta, and the circumference
connecting these points has been termed the sinotubular junction, which may also be described
as the portion of the great vessel separating the sinuses of Valsalva from the adjacent tubular
portion of the great artery.
Each of the ventricular surfaces of the semilunar cusps has a small nodule (noduli Arantii) in
the center of the free edge marking the contact sites of closure. Behind each cusp the vessel wall
bulges outward, forming a pouchlike dilatation known as the sinus of Valsalva.
The free edge of each cusp is concave, with a nodular interruption at the center of the cusp,
the nodulus Arantii. The portion of the cusp adjacent to the rim is not as thick and may normally
contain small perforations (Fig.3).

Fig.3. Perforations of the right (a) and left (c) cusps of the aortic valve

During ventricular systole, the cusps are passively thrust upward away from the center of the
aortic lumen. During ventricular diastole, the cusps fall passively into the lumen of the vessel as
they support the column of blood above. The noduli Arantii meet in the center and contribute to
the support of the leaflets. The geometry of the cusps and the strong fibrous tissue support
provide excellent approximations of the cusps and prevent regurgitation of blood.
The aortic valve closes at some distance away from its free edge. The area between the line of
closure and the free edge in 15% of cases is fenestrated.
Abnormalities of aortic valve:
- Aortic stenosis: in which the valve fails to open fully, thereby obstructing blood flow out
from the heart.It can be caused as a result of rheumatic fever, degenerative calcification, and
congenital diseases such as bicuspid aortic valve.
- Aortic insufficiency, also called aortic regurgitation: in which the aortic valve is incompetent
and blood flows passively back to the heart in the wrong direction. It can be caused as a result of
aortic regurgitation include dilation of the aorta, previous rheumatic fever, infection,
i.e. infective endocarditis, myxomatous degeneration of the aortic valve, and Marfan's syndrome.
Bicuspid aortic valve: is the most common congenital abnormality of the heart, in this condition,
- instead of three cusps, the aortic valve has two cusps.

98

Conclusions
1. The valvular apparatus of the left heart shows the large individual variability.
2. A number of studies have shown: a) variability of size of the casps; b) variability of the
number of the chordae tendineae; c) difference in the position of the coronary foramina; d) the
presence of additional skullops; e) presence of clefts and perforations of the leaflets.

1.

2.
3.
4.
5.

Bibliography
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the human aortic valve. Mechanics of composite materials. Volume 20, Number
5 (1985), 637-647.
Nayar S., Nayar P.G., Kherian K.M.. Heart valve structure: a predisposing factor for
rheumatic heart disease. Heart, 2006, 92: 1151-1152.
Patil D., Mehta C., Prajapati P.. Morphology of Mitral valve in Human cadavers. The Internet
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Robert B. Hinton and Katherine E. Yutzey. Heart Valve Structure and Function in
Development and Disease Annual Review of Physiology, 2011, Vol. 73: 29-46.
Thubrikar M., Nolan S.P., Bosher L.P., Deck J.D. The cyclic changes and structure of the
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99