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1
CELULELE STELATE HEPATICE I TERAPIA
ANTIFIBROTIC DIN BOALA CRONIC
HEPATIC
Hepatic stellate cells and antifibrotic therapy
in chronic liver disease
Dr. Alin Gabriel Ionescu, Conf. Dr. Cristin Constantin Vere,
Dr. Costin Teodor Streba, Prof. Dr. Ion Rogoveanu
Universitatea de Medicin i Farmacie, Craiova
REZUMAT
Fibroza hepac este un proces complex cu consecine negave asupra funciei i morfologiei hepace, putnd
determina apariia insucienei hepace i a hipertensiunii portale. Totodat, broza hepac este considerat o stare
precanceroas. Acvarea celulelor stelate hepace (CSH) reprezint principalul fenomen n apariia brozei hepace,
asel nct cele mai importante strategii anbroce vizeaz acvitatea acestor celule prin inhibarea acvrii, neutralizarea
rspunsului sau smularea apoptozei lor, dar i prin creterea degradrii matrixului extracelular (MEC). Strategiile
terapeuce viitoare urmresc ulizarea de preparate orale, bine tolerate la administrare ndelungat, care previn apariia
brozei i favorizeaz remanierea esutului cicatriceal. De asemenea, se are n vedere descoperirea de ageni terapeuci
noi a cror administrare parenteral poate produce efecte benece i sigure.
Cuvinte cheie: broza hepac, celule stelate hepace, terapie anbroc
ABSTRACT
Liver brosis is a complex process with negave outcomes regarding liver funcon and morphology, which may lead to
hepac insu ciency and portal hypertension. Liver brosis is also considered a precancerous state. Hepac stellate cells
(HSC) acvaon represents the main event in the development of liver brosis; therefore the most important anbroc
strategies target these cells by inhibing their acvaon, neutralizing their response or their apoptosis smulaon, while
also increasing the degradaon of the extracellular matrix (ECM). Future therapeuc strategies target the use of oral
medicaon, well tolerated aer long administraon, which prevents the development of liver brosis and favorise the
regression of scar ssue. Also, new therapeuc agents are to emerge, whose parenteral administraon may produce
benec and sure eects.
Key words: liver brosis, hepac stellate cells, anbroc therapy
Adresa de coresponden:
Conf. Dr. Cristin Constantin Vere, Universitatea de Medicin i Farmacie, Str. Petru Rare, Nr. 2-4, Cod 200349, Craiova, Dolj
INTRODUCERE
Fibroza hepatic este un proces dinamic aprut
ca urmare a producerii n exces i a reducerii degra-
drii proteinelor MEC. Apariia brozei hepatice
duce la diminuarea schimburilor metabolice dintre
sinusoidele hepatice i hepatocite, la formarea un-
turilor porto-venoase, la nlocuirea parenchimului
prin mezenchim, acestea avnd drept consecine
reducerea funciei hepatocitare, apariia hiper ten-
siunii portale, a varicelor esofagiene, a tulburrilor
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Practica Farmaceutic Vol. 4, Nr. 3-4, An 2011
de coagulare, ascitei, edemelor, hemoragiei digestive
superioare i instalarea encefalopatiei.
Totodat, broza hepatic este considerat ca o
stare ce precede apariia carcinomului hepatocelular
(CHC), n prolaxia cruia un element fundamental
l reprezint controlul i reversibilitatea acesteia
(1,2).
CSH sunt localizate n spaiul Disse, ntre hepa-
tocite i sinusoidele hepatice. n catul sntos,
rolul lor principal este depozitarea vitaminei A, pre-
cum i sinteza ctorva componente ale MEC. Le-
zarea hepatic determin eliberarea de citokine de
ctre celulele inamatorii, celulele Kupffer i hepa-
tocitele displastice. Activarea CSH reprezint feno-
menul principal n apariia brozei hepatice, ind
totodat principala int terapeutic a strategiilor
antibrotice (3,4,5).
STRATEGIILE TERAPEUTICE
ANTIFIBROTICE
Exceptnd terapia bolii primare i prevenirea le-
zrii hepatocitare, majoritatea strategiilor anti brotice
vizeaz inhibarea activitii CSH prin: redu cerea
inamaiei sau a rspunsului inamator imun al
gaz dei; reducerea activrii CSH; neutralizarea rs-
punsului proliferativ, brogenetic contractil i/sau
proinamator; inducerea apoptozei CSH.
Alte strategii antibrotice urmresc creterea
degradrii MEC, att prin stimularea celulelor care
produc matrix-metaloproteaze (MMPs), ct i prin
blocarea inhibitorilor tisulari de metaloproteaze
(TIMPs) sau prin administrarea direct de MMPs
(vezi Tabelul 1).
INHIBAREA ACTIVRII CELULELOR
STELATE HEPATICE
Inhibarea transformrii CSH inactive n mio-
broblati activai reprezint o int terapeutic att
n boala hepatic, ct i n rspunsul brotic.
Deoarece stresul oxidativ are rol n stimularea
activrii CSH, reducerea acestuia ar reprezenta o
posibil strategie terapeutic.
O serie de studii experimentale, efectuate att in
vivo, ct i in vitro, au evideniat rolul inhibitor al
Tabelul 1. CSH i strategiile terapeuce anbroce
Inhibarea acvrii celulelor stelate hepace
Anoxidani: vitamina E, fosfadilcolina, silimarin, resveratrol
IGF-1
Citokine: -interferon, factorul hepatocitar de cretere
Liganzi PPAR gamma
Inhibitori de lepn
Adiponecna antagonist de TNF-
Antagonist Smad7 de TGF-
Inhibitor de rozinkinaz PTK/ZK pentru PDGF i TGF-
Pentoxilina
Antagonist DKK-1 al cii de semnalizare Wnt
Inhibitori de histone diacelaz (HDAC)
Neutralizarea rspunsului celulelor stelate hepace
Anproliferave Anbrinogenice Ancontracle
Antagoni ai receptorilor
citokinelor (ex. PDGF)
Inhibitori ai sintezei de colagen Ancorpi umanizai Antagoni ai receptorilor de
endotelin
Inhibitori de Tirozin-kinaz Halofuginone Inhibitori ai sistemului renin-
angiotensin
Oxid nitric agonist/donor
Inhibitori de Lipoxigenaz Inhibitori prolil hidroxilaz Factorul de cretere hepatocitar -
Simvastan Antagoni TGF- Interleukina-10 -
Pentoxilina Receptori solubili Inhibitori de colagen
translaional
-
PI3K Inhibitori de rozin kinaz
(camostat mesilatul)
Relaxina -
Rapamicina Decorin, manozo 6 fosfat solubil Inhibitor HSP47 -
- Inhibitori Rho Ansens al lanului B al PDGF -
Smularea apoptozei celulelor stelate hepace
Antagoni TIMPs
Celulele natural killer
Glitoxina
Bortezomibul
Factorul de cretere hepatocitar
Creterea degradrii matrixului cicatriceal
Antagoni TGF-
Acvatorul plasminogen de p urokinaz
Relaxina
Administrare de matrix metaloproteaze
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unor antioxidani precum vitamina E, silimarina,
fosfatidilcolina i S-adenosyl-L-metionina n acti-
varea CSH (6,7,8). Aceti antioxidani asigur pro-
tecia hepatocitelor mpotriva apoptozei i reducerea
brozei hepatice.
Au fost descrii numeroi factori care scad gradul
brozei hepatice. Astfel, Canturk i colab. au evi-
den iat reducerea brogenezei ca urmare a dimi-
nurii stresului oxidativ prin experimente pe obo-
lani crora li s-a indus ciroz hepatic prin ligaturarea
ductului biliar comun, i ulterior li s-a administrat
IGF-1, un reglator important al metabolismului in-
termediar (9).
Efectele inhibitorii ale citokinelor interferon- i
ale factorului de cretere hepatocitar (HGF) asupra
CSH au fost observate pe modele experimentale
animale, unde gradul de activare al CSH a fost redus
semnicativ (10). Mecanismul antibrotic al HGF
este incert, dar se pare c acioneaz prin inhibarea
activitii factorului de cretere hepatocitar (TGF-
1) (11).
Thiazolidindionele, o clas de medicamente uti-
li zate n diabet, n special cele din generaiile a II-a
i a III-a (troglitazonele), care prezint hepatoto xi-
citate redus, au avut efecte benece n boala he-
patic (12). Thiazolidindionele sunt liganzi sintetici
ai receptorilor nucleari PPAR gamma identicai la
nivelul CSH i acioneaz prin reducerea activrii
CSH (13,14).
Insulinorezistena intervine n patogeneza i
progresia bolii hepatice non-alcoolice i a hepatitei
cronice virale, prin intermediul leptinei i adipo-
nectinei.
Leptina, o adipocitokin cu rol n metabolismul
glucidic i n procesul de vindecare, prezint mai
multe proprieti probrogenetice (15,16,17), prin
stimularea sintezei de colagen I 2 (18,19), a crui
acumulare excesiv reprezint trstura denitorie
a brozei hepatice. Leptina inhib sinteza i acti vi-
tatea MMP-1 i stimuleaz producerea de TIMP-1
(20, 21, 22). De asemenea, leptina menine CSH n
stadiul activat prin stimularea proliferrii i prin
inhibarea apoptozei. Saxena i colab. au evideniat
reducerea leziunilor i a brozei hepatice la anima-
lele de laborator cu decit de leptin (23).
Nivelurile serice de adiponectin, un hormon
pro teic secretat de adipocite, sunt reduse la obezi,
ducnd la apariia insulinorezistenei. Adiponectina
poate contracara insulinorezistena prin antago-
nizarea TNF- i scderea nivelului seric al glucozei
i al trigliceridelor (24). Un studiu efectuat pe oa-
reci a artat c administrarea adiponectinei deter-
min o reducere a leziunilor hepatice cauzate de
alcool, prin diminuarea veziculelor lipidice de la
nivelul hepatocitelor induse de consumul de etanol
(25). Terapia antibrotic din boala hepatic poate
viza aceste ci patogenice.
Importana cilor de semnalizare mediate de TGF-
i de factorul de cretere derivat din trombocite
(PDGF), caracteristice apariiei brozei hepatice i
tumorogenezei, a fost relevat de mai multe studii
(26). Astfel, Mikula i colab. au demonstrat c in-
tervenia genetic la nivelul cii de semnalizare me-
diate de ctre TGF- din hepatocite prin intermediul
antagonistului Smad7 determin o reducere a gra-
dului brozei hepatice i a progresiei tumorale dup
interaciunea cu CSH (27).
Liu i colab. au artat c PTK/ZK, un puternic
in hibitor de tirozinkinaz, blocheaz cile de sem-
nalizare mediate de PDGF i TGF- la nivelul CSH
i inhib astfel brogeneza la nivel hepatic (28).
n condiii ziologice, CSH sintetizeaz colagen
III, IV i cantiti mici de colagen I (29). n timpul
procesului de brogenez hepatic, CSH devin
prin cipalele celule productoare de matrix extra-
celular, cu o pondere semnicativ n producia de
colagen I (30, 31). Pentoxilina este un derivat me-
til xantinic cu proprieti antibrotice care determin
reducerea sintezei de I colagen de ctre CSH ac-
tivate prin inhibarea degradrii de I kappa b , care
la rndul su blocheaz activarea factorului nuclear
kappa-B (NF-kB) (32).
O serie de autori au artat c o alt cale de
semnalizare posibil implicat n apariia brozei
hepatice este calea Wnt, care intervine n broza
pulmonar i renal. Cheng i colab. au evideniat
c prin blocarea acestei ci de semnalizare cu
ajutorul Dickkopf-1 (DKK-1), un antagonist al co-
receptorului Wnt, se realizeaz o reducere a gradului
brozei hepatice (33).
Mai multe studii ce au vizat nelegerea reglrii
transcripionale au evideniat posibilitatea inhibrii
CSH activate prin blocarea activitii histon-dia-
cetilazei (HDACs), enzim cu rol major n modi-
carea cromatinei n timpul transcripiei genetice.
Inhibitorii cu mare specicitate pentru HDACs ofe-
r o modalitate selectiv de blocare a activrii CSH
(34).
NEUTRALIAREA RSPUNSULUI
PROLIFERATIV, FIBRO GENIC CONTRACTIL
I/SAU PROINFLAATOR AL CELULELOR
STELATE
O alt int a terapiei antibrotice urmrete blo-
carea etapelor de proliferare, de brogenez sau a
rspunsului contractil al CSH cu ajutorul anta go-
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Practica Farmaceutic Vol. 4, Nr. 3-4, An 2011
nitilor receptorilor citokinici. Progresele realizate
n descifrarea rolului factorului de cretere au dus
la descoperirea antagonitilor citokinelor i a recep-
torilor lor. Evidenierea importanei unor citokine
proliferative n patogenia brozei hepatice ce in-
tervin n cile de semnalizare ale CSH, precum
PDGF, factorul de cretere al broblatilor, i al
interveniei TGF- pe receptorii tirozinkinazei au
dus la apariia unor inhibitori care s blocheze aces-
te ci de semnalizare. n acest fel au fost descoperii
inhibitori ai acidului gamma-linoleic, ai lipooxi-
genazei i ai receptorilor PPAR gamma (35, 36).
Okuno i colab. au observat c administrarea
camostat mesylatului, care determin scderea
TGF- activat, duce la o diminuare a progresiei
brozei hepatice la obolani (37). Un studiu ulterior,
efectuat pe oareci, a artat c imatinib mesilatul,
un inhibitor de receptor de tirozinkinaz, determin
o reducere a gradului brozei hepatice prin scderea
semnicativ a proliferrii i a migraiei CSH, in-
duse de PDGF-BB, precum i o diminuare att a
-SMA, ct i a expresiei 2-(I)-procolagen mRNA
n celulele stelate hepatice activate (38).
Utilizarea antagonitilor TGF- de tipul anticor-
pilor monoclonali i inhibitorilor de proteaze de-
termin att inhibiia produciei de MEC, ct i ac-
celerarea degradrii lui. Dintre inhibitorii proteazici
s-a folosit manozo-6-fosfat (M-6-P) recombinat
solubil care se xeaz pe receptorul M-6-P ce leag
TGF pe suprafaa CSH n timpul activrii lor de la
stadiul latent (39). Administrarea pe termen lung a
antagonitilor TGF- la oameni poate favoriza apa-
riia carcinomului hepatocelular, prin alterarea mo-
dulrii inamaiei i a rspunsului imun, cu pierderea
inhibiiei de cretere controlat de TGF- (40).
O alt strategie terapeutic ar putea reprezentat
de inhibarea sistemului renin-angiotensin. Inhi-
bitorii de renin-angiotensin sunt utilizai ca ageni
antibrotici n cazul pacienilor cu boal cronic
renal i cardiac, fr a determina apariia efectelor
adverse la administrarea pe perioade ndelungate.
Un studiu efectuat pe dou loturi de pacieni cu
hepatit cronic viral C i steatohepatit non-al-
coolic a evideniat efectele benece ale inhibitorilor
de renin-angiotensin n prevenirea apariiei -
brozei hepatice (41).
Son i colab. au demonstrat c CSH supuse ac-
iunii unui adenovirus ce codic o form negativ
dominant de fosfatidilinozitol 3-kinaz (PI3K),
controlat de un promoter de -SMA, prezint o di-
minuare a proliferrii, migraiei, sintezei de colagen,
precum i reducerea activitii unor gene constituente
probrogenetice adiionale. Acest adenovirus in-
duce, totodat, apoptoza celular (42).
Cho i colab. au evideniat, prin experimente pe
obolani, efectul benec al unor vasodilatatoare de
tipul prostaglandinei E2 i oxidului nitric n terapia
antibrotic. Acestea acioneaz prin blocarea re-
ceptorilor endotelinei-A, determinnd reducerea
gra dului de broz hepatic prin blocarea sintezei
i a depunerii de colagen (43).
n ultimii ani s-a urmrit descoperirea de mo-
lecule cu greutate mic care, prin blocarea recep-
torilor citokinelor sau a cilor de semnalizare intra-
ce lular inhib brogeneza hepatic. Astfel de
mo lecule sunt un inhibitor selectiv al adeziunii
focale Rho mediate (44) i un antisens al lanului B
al PDGF care reduc broza hepatic indus expe-
rimental (45).
HSP 47 este o caperon de colagen prezent n
CSH activate, a crei concentraie n reticulul endo-
plasmic se coreleaz semnicativ cu creterea sin-
tezei de colagen (46, 47). Administrarea de lipozomi
ce conin vitamina A i ARN, care inhib HSP 47,
blocheaz sinteza de colagen de ctre CSH activate
(48).
O alt posibilitate terapeutic n vederea reducerii
progresiei brozei hepatice ar putea reprezentat
de utilizarea rapamicinei, un imunosupresor admi-
nistrat posttransplant hepatic, care inhib prolifera-
rea CSH (49), ns care are dezavantajul creterii
ris cului de apariie a trombozei arterei hepatice
dup administrarea ndelungat (50).
Bennett i colab. au observat c administrarea
re laxinei, un hormon peptidic natural cu receptori
prezeni pe suprafaa mai multor celule, inclusiv
CSH (51), are ca efect att scderea sintezei de co-
la gen de ctre CSH activate, ct i creterea de-
gradrii matrixului extracelular att in vivo, ct i in
vitro.
STIULAREA APOPTOEI CELULELOR
STELATE HEPATICE
Apoptoza este mecanismul principal responsabil
de reducerea numrului de CSH activate n timpul
vindecrii leziunii hepatice (52). Mai muli mediatori
ai apoptozei de tipul Fas/FasL, receptori TNF,
precum i Bcl/Bax, au fost identicai n CSH, astfel
nct o posibil int terapeutic ar putea viza de-
clan area apoptozei prin intermediul acestor me-
diatori (53, 54).
Studii experimentale i noi dovezi clinice au
artat c att broza, ct i ciroza hepatic sunt
potenial reversibile prin iniierea apoptozei CSH,
ndeprtndu-se astfel celula responsabil att de
producerea de MEC, ct i de protecia MMPs prin
producerea de TIMPs.
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Acumularea de MEC i afectarea remanierii
aces tuia reprezint cauza principal a progresiei
brozei hepatice. MMP-1 este principala proteaz
care poate degrada colagenul de tip I, principala
form de colagen din catul brotic (55). Inactivarea
MMPs se realizeaz prin legarea de TIMPs (56).
CSH activate sintetizeaz n exces TIMP-1 i TIMP-
250 care inhib colagenazele interstiiale, ducnd la
reducerea degradrii de MEC i la acumularea aces-
tuia. TIMP-1 are i un efect antiapoptotic asupra
CSH (57).
Antagonitii TIMPs reprezint o int terapeutic
pentru a inhiba sinteza de colagen I i a declana
apop toza CSH activate. TIMP-1 are un rol major n
supravieuirea CSH prin blocarea direct a apoptozei
acestor celule, astfel nct antagonitii TIMP de-
termin o diminuare a brozei (58).
Celulele natural killer (NK) intervin n imunitatea
nnscut i au rol n limitarea brozei hepatice prin
neutralizarea CSH activate (59, 60) i prin eliberarea
a dou citokine antibrotice INF i INF (61, 62).
Consumul de alcool reduce ecacitatea NK, ceea ce
are ca efect o accelerare n progresia brozei hepa-
tice (63).
Administrarea glitoxinei, un metabolit fungic, la
obolan a indus apoptoza CSH, n absena stresului
oxidativ, prin eliberarea citocromului c mitocondrial
i prin activarea caspazei-3 i depleia de ATP, res-
ponsabile de reducerea brogenezei (64).
Anan i colab. au demonstrat c bortezomibul,
un inhibitor de proteaz, induce apoptoza CSH prin
blocarea activitii NFB, crescnd timpul de n ju-
mtire al inhibitorilor acestuia (65).
O alt potenial int terapeutic este reprezentat
de terapia cu citokine. Astfel, administrarea experi-
mental a factorilor de cretere prin intermediul te-
rapiei genice a dus la o reducere a brozei hepatice.
ntr-un studiu efectuat pe obolani crora li s-a in-
dus ciroz hepatic prin intermediul dimetilnitro-
zaminei, s-a observat c administrarea HGF a dus la
reducerea proliferrii i iniierea apoptozei celulelor
hepatice SMA pozitive (66).
STIULAREA I INTENSIFICAREA
DEGRADRII ATRIULUI CICATRICEAL
Un rol major n terapia antibrotic este repre-
zentat de resorbia MEC deja existent, prevenind
astfel progresia brozei. Antagonitii TGF-, care
stimuleaz sinteza de MEC prin stimularea CSH,
produc degradarea matrixului prin reglarea TIMPs
i prin creterea activitii colagenazei interstiiale.
Un studiu in vivo efectuat pe animale de laborator
ce a urmrit activatorul plasminogen de tip urokinaz
a evideniat resorbia MEC (67).
STRATEGII TERAPEUTICE VIITOARE
Descoperirea de noi terapii antibrotice se ba-
zeaz pe aprofundarea cunotinelor despre mecanis-
mele ziopatologice implicate n apariia leziunilor
hepatice i n activarea CSH.
Terapia ideal ar trebui s e reprezentat de pre-
parate orale, bine tolerate la administrare ndelun-
gat, care nu doar previn apariia brozei, ci deter-
min i remanierea esutului cicatriceal, ducnd la
stabilizarea sau la mbuntirea funciei hepatice.
Pe lng terapia oral, se are n vedere i trata-
mentul parenteral, preferabil cu administrare spt-
m nal sau lunar n bolile cronice. n acest sens, se
urmrete administrarea de anticorpi monoclonali
care pot produce efecte benece i sigure.
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