Sunteți pe pagina 1din 8

ARTICOLE ORIGINALE

1
EFECTELE ANTIINFLAMATORII ALE
NICOTINEI
Anti-inflammatory effects of nicotine
Dr. Corina-Daniela Ene1, Prof. Dr. Mircea Penescu1,2, Dr. Ilinca Nicolae2,
Prof. Dr. Emanoil Ceauu2
1
Spitalul Clinic de Nefrologie Carol Davila, Bucureti
2
Spitalul Clinic de Boli Infecioase i Tropicale Victor Babe,
Universitatea de Medicin i Farmacie Carol Davila, Bucureti

REZUMAT
O serie de date epidemiologice i experimentale au dovedit c nicotina stimuleaz un rspuns antiinflamator
n esuturi extraneuronale, mediat de receptorii nicotinici homopentamerici alfa7nAChR, localizai cu pre-
cdere pe celule imune i inflamatorii. Acest mecanism farmacologic prin care procesul inflamator poate fi
reglat prin folosirea unor agoniti sau antagoniti nicotinici selectivi a fost numit calea nicotinic antiinfla-
matorie. Tratamentul cu nicotin iniiaz o serie de evenimente intracelulare asociate cu stimularea mai
multor ci de semnalizare: NFkB, JAK/STAT, MyD88/ TLRs, MAPKs/ERKs. Cunoaterea mecanismelor anti-
inflamatorii mediate de alfa7nAChR este util pentru valorificarea potenialului terapeutic al nicotinei n re-
glarea rspunsului inflamator n anumite procese patologice.

Cuvinte cheie: nicotin, potenial antiinflamator, receptori alfa7nAChR,


afeciuni inflamatorii

ABSTRACT
A number of epidemiological and experimental data have shown that nicotine stimulates anti-inflammatory
response in extraneuronal tissues, response mediated by homopentameric nicotinic receptors, 7nAChR- al-
pha. The receptors are located mainly on immune and inflammatory cells. These pharmacological mecha-
nisms, through which inflammatory process could be adjusted is the use of selective nicotinic agonists and
antagonists, called anti-inflammatory. Treatment with nicotine initiates a series of intracellular events associ-
ated with stimulation of several signaling pathways: NFkB, JAK/STAT, MyD88/TLRs, MAPKs/ERKs. Knowl-
edge of anti-inflammatory mechanisms mediated by alpha7nAChR is useful for valuing the therapeutic poten-
tial of nicotine in regulating the inflammatory response in certain pathological processes.

Keywords: nicotine, the anti-inflammatory capacity, alpha7nAChR receptors,


inflammatory disorders

INTRODUCERE mator este reprezentat de activarea sistemului


nervos parasimpatic. Sistemul nervos colinergic,
Inflamaia este un rspuns biologic complex care acioneaz prin intermediul nervului vag, pre-
prin care organismul reacioneaz la agresiune (mi- vine eliberarea excesiv a citokinelor proinflama-
croorganisme patogene, ageni fizici, ageni chi- torii i atenueaz inflamaia local i sistemic.
mici, ageni imunologici, distrucii tisulare). n Cunoaterea mecanismelor antiinflamatorii me-
condiii normale, rspunsul inflamator este bine diate de acetilcolin i agoniti colinergici este util
controlat de organism, ns un rspuns inflamator pentru valorificarea potenialul terapeutic al cii
exagerat poate duce la distrugerea esuturilor, boli colinergice n combaterea inflamaiei locale sau
autoimune sau sepsis. Un mecanism natural prin sistemice din anumite procese patologice.
care organismul uman poate regla procesul infla-

Autor corespondent:
Dr. Corina-Daniela Ene, Spitalul Clinic de Nefrologie Carol Davila, Calea Griviei nr. 4, Bucureti
E-mail: koranik85@yahoo.com

REVISTA ROMN DE BOLI INFECIOASE VOLUMUL XVIII, NR. 1, AN 2015 5


6 REVISTA ROMN DE BOLI INFECIOASE VOLUMUL XVIII, NR. 1, AN 2015

CALEA NICOTINIC ANTIINFLAMATORIE


Acetilcolina (Fig. 1), neurotransmitorul prin-
cipal al nervului vag, stimuleaz un rspuns antiin-
flamator mediat de receptorii muscarinici (mAChR)
i nicotinici (nAChR) ai acetilcolinei (calea coliner-
gic antiinflamatorie (1). Din punct de vedere far-
macologic, s-a dovedit c agoniti nicotinici selec-
tivi ai nAChR (nicotina Fig. 2, GTS-21 Fig. 3,
PNU 282987 Fig. 4) sunt mai eficieni dect ace- FIGURA 4. PNU 282987- N-[(3'R)-1'-azabiciclo[2.2.2]
oct-3- yl] -4-clorobenzamida-C14H17ClN2O
tilcolina n reglarea producerii de citokine i sem-
nalizarea rspunsului antiinflamator. Acest meca-
nism farmacologic prin care procesul inflamator n timp ce tratamentul cronic suprim rspunsurile
poate fi reglat prin utilizarea agonitilor selectivi ai imune i inflamatorii. S-a raportat c fumatul este
alpha7nAChR a fost numit calea nicotinic anti- asociat cu o inciden crescut a infeciilor respi-
inflamatorie (2-6). ratorii acute, parodontit, meningit bacterian, ar-
trit reumatoid, boal Crohn, lupus eritematos sis-
temic, psoriazis, ateroscleroz, boli pulmonare ob-
structive cronice, cancer pulmonar, boli coronariene.
Nicotina protejeaz rinichii de prejudiciul cauzat
de ischemie i reperfuzie. n plus, nicotina ar putea
diminua incidena i severitatea mai multor boli in-
FIGURA 1. Acetilcolin - (2-Acetoxi etil) - flamatorii (colit ulcerativ, diverticulit, boala ce-
trimetilamoniu - C7H16NO2 liac, diabet) i neurodegenerative (boala Parkinson,
unele forme ale bolii Alzheimer) (2,3,7,8).
Activarea farmacologic a cii nicotinice a fost
dovedit n: leziuni inflamatorii renale (3-5,9-12),
boli inflamatorii intestinale (13), boli autoimune
(14,15), boli infecioase (7,16), afeciuni pulmonare
(17-27) (Tabelul 1).

FIGURA 2. Nicotina - 3- (2-(N-metilpirolidinil))piridina -


RECEPTORII NICOTINICI Alfa7nAChR
C10H14N2
Activitatea anti-inflamatorie a nicotinei se reali-
zeaz prin intermediul receptorilor homopentame-
rici alfa7nAChR. Subunitatea alfa7 a receptorilor
nicotinici ai acetilcolinei este codificat de gena
Chrna7, situat n regiunea cromozomial 15q14.
Proteina alfa7 are 56KDa i 502 aminoacizi i con-
ine n structura sa:
un peptid semnal de 22 de aminoacizi loca-
lizat la extremitatea N-terminal;
un domeniu de legare a ligandului extracelular
de 200 de aminoacizi;
domenii transmembranare T1-T4 care traver-
seaz bistratul lipidic i formeaz un canal
FIGURA 3. GTS21-[(3E)-3-[(2,4-dimetoximetiliden]-5,6- ionic permeabil pentru sodiu i calciu;
dihidro-4H-piridin-2-il]piridin- C19H20N2O2 un domeniu intracelular situat ntre T3 i T4.
Aminoacizii Tyr-386 i Tyr-442 situai n
Nicotina este principalul constituent imunosu-
domeniul citoplasmatic al subunitii alfa7,
presor din fumul de igar care inhib rspunsurile
joac rol n activarea receptorului. Fosfori-
imune nnscute i adaptative. Efectele acute i cro-
larea tirozinei din poziiile 386 i 442 de
nice ale nicotinei asupra sistemului imun sunt, de
ctre kinazele Src inhib activarea
obicei, opuse. O serie de constatri recente su-
alfa7nAChR (1,28).
gereaz c tratamentul acut cu nicotin stimuleaz,
REVISTA ROMN DE BOLI INFECIOASE VOLUMUL XVIII, NR. 1, AN 2015 7

TABELUL 1. Efectele modulatoare ale cii nicotinice antiinflamatorii n boli inflamatorii


Model Prejudiciu Efecte
Ischemie/reperfuzie renal Leziuni tubulare Protecia funciei renale i limitarea leziunilor tubulare dup ischemie/
(oarece) reperfuzie:
Nicotina a mpiedicat infiltrarea neutrofilelor, a sczut producerea TNF, KC,
HMGB1, a redus expresia moleculelor de adeziune (VCAM, ICAM, Eselectina i
CD44);
Nicotina a sczut proliferarea i apoptoza celulelor epiteliale tubulare dup
ischemia/reperfuzia renal
Leziuni renale acute LPS induse Sepsis Efecte renoprotectoare:
(om, oarece) Nicotina i GTS21 au supresat inflamaia local i sistemic prin NFkB, via Ikb
i activitatea proteozomal.
Glomerulonefrite (obolan) Proteinurie indus Efecte renoprotectoare:
spontan Nicotina a redus glomeruloscleroza, inflamaia i fibroza interstiial;
Nicotina a mbuntit clearance-ul creatinin i proteinuria.

Boli renale cronice (obolan) Nefropatie diabetic Fumatul promoveaz progresia nefropatiei diabetice prin creterea citokinelor
profibrotice (fibronectina, TGF, colagen), proliferarea i hipertrofia celulelor
mezangiale
Colita acut DSS indus, colita Culturi celulare, modele Nicotina amelioreaz colita i reduce tumorigeneza prin supresia IL6/STAT3/
cronic tumorale TNF
Artrita reumatoid Culturi celulare Efect protector:
Nicotina i GTS21 limiteaz inflamaia asociat artritei reumatoide;
GST21 reduce diferenierea Th1 i nivelul factorului de transcripie TBX21 n
celule TCD4+
Lupus eritematos sistemic Model experimental Efect protector:
(oarece) Nicotina a suprimat inflamaia sistemic i a redus tensiunea arterial la
oarecii cu lupus eritematos sistemic prin stimularea alfa7nAChR.
Boli infecioase Modele umane i Nicotina reduce inflamaia prin activarea GSK3
experimentale
Leziuni pulmonare acute induse Efect direct asupra Aciune protectoare prezent:
de HCl (oarece, obolan) celulelor epiteliale Nicotin, colin, PNU-282987 (agonist farmacologic specific al alpha7nAChR)
pulmonare au indus activarea alpha7nAChR
Leziuni pulmonare acute induse Aciune direct asupra Aciune protectoare prezent:
de LPS (oarece) celulelor epiteliale Nicotina a redus recrutarea leucocitelor, a sczut activitatea
pulmonare mieloperoxidazic;
Nicotina a supresat IL1, IL6, TNF, MIP1/CCL3,MIP2/CXCL2, eotaxina/CCL11;
Nicotina a atenuat RNAm IL6, IL1, TNF n macrofage de oarece stimulate;
GTS21 a provocat scderea TNFalpha

Pneumonie asociat cu E. Coli Aciune direct asupra Efect protector prezent:


(oarece) celulelor epiteliale Agonitii alfa7nAChR au redus producerea MIP2 i migraia neutrofilelor, au
pulmonare indus leziuni pulmonare grave la oarecii cu deficit de alfa7nAChR, au sczut
mortalitatea i prejudiciul pulmonar la oarecii de tip slbatic.
Pneumonie asociat cu Aciune direct asupra Efect protector absent.
P. aeruginosa (oarece) celulelor epiteliale PNU-282987 a amplificat leziunile pulmonare, a sczut eliberarea
pulmonare chemoatractantului keratinocitar, a crescut viabilitatea bacteriilor intracelulare
Pneumonie asociat cu Aciune direct asupra Efect protector absent:
Streptococcus pneumoniae celulelor epiteliale Tratamentul cu nicotin a crescut numrul de bacterii Gram pozitive n
(oarece) pulmonare plmni i snge;
La oarecii tratai cu nicotin s-a observat amplificarea inflamaiei pulmonare
la 24 ore dup inocularea bacteriei;
Nicotina a indus creterea citokinelor proinflamatorii (TNF alfa, IFN gamma)

Peritonit pulmonar acut Aciune indirect asupra Efect protector absent:


(obolan) celulelor endoteliale Administrarea nicotinei a crescut infiltrarea PMN i mortalitatea oarecilor;
pulmonare Nicotina a redus clearence-ul bacteriilor intracelulare.

Leziuni pulmonare induse prin Efect direct asupra Efect protector absent:
ventilaie mecanic (oarece, celulelor epiteliale PNU-282987 a sczut numrul leziunilor pulmonare, concentraia substanei
obolan) pulmonare P i coninutul pulmonar i plasmatic al IL6
GTS21 a atenuat eliberarea TNF alfa.

Leziuni pulmonare acute Efect direct asupra Efect protector absent;


asociate cu virusul gripal celulelor epiteliale Nicotina a suprimat migrarea leucocitelor n focarul infecios/inflamator i a
(oarece). pulmonare. crescut titrul virusului la nivel pulmonar.

Alfa7nAChR: Homopentaalpha7subunit nicotinic acetylcholine receptors; TNF: Tumor necrosis factor; KC: Kerotinocyte
chemoattractant; HMGB1: High-mobility group box 1 protein; VCAM: Vascular cell adhesion protein; ICAM: Intercellular adhesion
molecule; LPS: Lipopolysaccharide; GTS: 3-(2,4-dimethoxybezylidone)-anabaseine dihydrocloride; NFkB: Nuclear factor kappa-light-
chain-enhancer of activated B cells; IkB: Inhibitor of nuclear factor kB; IL: Interleukin; TGF: Transforming growth factor; IFN:
Interferon; STAT: Signal transducer and activator of transcription; DSS: Dextran sulfate sodium; TBX: T-box proteins; GSK: Glycogen
synthase kinase; PNU: N-azobicycle-clorobenzamide; MIP: Monocyte inflammatory protein; CCL: Chemokine(C-C motif) ligand;
CXCL: Chemokine (C-X-C motif) ligand; PMN: Polymorphonuclear cells.
8 REVISTA ROMN DE BOLI INFECIOASE VOLUMUL XVIII, NR. 1, AN 2015

S-au identificat receptori alfa7nAChR funcio- Stimularea alfa7nAchR cu acetilcolin sau nicotin
nali, sensibili la nicotin, n numeroase celule induce semnalizarea n limfocitele T prin externa-
imune i inflamatorii, dintre care amintim: macro- lizarea citoplasmatic a calciului intracelular i sti-
fage (17,29,30-32), monocite (17,33,34,64), neu- mularea c-fos (57-59). Activarea alfa7nAChR am-
trofile (19,30,35), mononucleare (17,36), celule plific apoptoza celulelor T indus de cortizol (57).
dendritice (17,37), limfocite B i T (17,30,38-41), Tratamentul cu nicotin a crescut numrul limfo-
celule epiteliale (17,30,42), celule endoteliale (17, citelor B n mduva osoas, a amplificat dezvoltarea
43,44), celule stem hematopoietice (17,63), celule i maturizarea limfocitelor. Activarea receptorilor
stem mezenchimale (17,45,46), celule progenitoare alpha7nAchR de ctre nicotin pe limfocitele B a
endoteliale (17,47,48), fibroblaste (17,49,50). fost influenat de exprimarea costimulatorului
Nicotina i/sau fumul de igar modific funciile CD40 pe aceste celule (60).
macrofagelor (pinocitoza, endocitoza, degradarea Nicotina regleaz eliberarea serotoninei ntr-o
intracelular a proteinelor fagocitate, capacitatea serie de celule extraneuronale. Nicotina i seroto-
de a ucide agenii patogeni). Se apreciaz c aceste nina coopereaz reciproc n elaborarea rspunsului
efecte ar putea fi atribuite acumulrii nicotinei n antiinflamator. Aceast interaciune este posibil
lizozomi, efect asociat cu alterarea capacitii aces- deoarece receptorii nicotinici colinergici i seroto-
tor organite de a produce digestia enzimatic (1). n ninergici sunt exprimai simultan pe celule B i T,
monocite i macrofage, nicotina afecteaz elibe- monocite, macrofage, celule dendritice, celule en-
rarea TNF, IL6, IL1beta, IL8, PGE2, CD14, IL12, doteliale. Nicotina i serotonina exercit efecte
TLR4 (58). n macrofage i neutrofile, nicotina mo- contrare asupra eliberrii de citokine de ctre ce-
dific producia de anioni superoxizi, chemotaxia, lulele din sngele periferic. Astfel, nicotina i sero-
producia de chemokine, expresia integrinelor, su- tonina au potenial inhibitor asupra eliberrii TNF
prim apoptoz. O serie de studii sugereaz ca tra- (n macrofage i monocite) i efecte opuse asupra
tamentul acut cu nicotin sau cu agoniti nicotinici producerii IL1beta i IFNgamma (n celule T i
determin reducerea inflamaiei, iar expunerea cro- NK). n plus, nicotina inhib producerea IL6, a
nic la nicotin ar putea favoriza dezvoltarea anu- IL18 (n monocite i macrofage) i a IL12 (n mo-
mitor infecii pulmonare la fumtori. Agonitii ni- nocite, macrofage i celule dendritice). n modele
cotinici au inhibat producerea citokinelor proinfla- experimentale de boli inflamatorii intestinale, s-a
matorii i au prevenit endotoxemia letal. Absena apreciat c nicotina regleaz diferenierea Th1/Th2
receptorilor nicotinici de pe suprafaa celular a i apoptoza (61-64).
fost asociat cu creterea sintezei i secreiei me-
diatorilor proinflamatori (29-32). GTS21 a atenuat SEMNALIZAREA ASOCIAT CU
expresia TNF, HMGB1, RAGEs n culturi de Alfa7nAChR
monocite i n sngele total stimulat cu endotoxin.
Antagonitii receptorilor nicotinici (alfa bungara- Administrarea de agoniti alfa7nAChR ar
toxina, mecamilamina) au inversat efectele inhibi- putea preveni producerea mediatorilor proinflama-
toare induse de nicotin n numeroase modele ex- tori n celule productoare de citokine. Activarea
perimentale (51-52). Nicotina a suprareglat in vitro alfa7nAChR n celulele imune i inflamatorii ame-
expresia i activitatea homopent alfa7nAChR i a lioreaz rspunsul inflamator prin mai multe meca-
modulat rspunsul inflamator n neutrofile, celule nisme posibile: reducerea translocrii nucleare a
dendritice, limfocite, celule epiteliale, celule endo- NFkB, activarea STAT3 printr-un proces de fos-
teliale, fibroblaste (30,42,44,45,49,50,53-56). n forilare mediat de JAK2, stimularea TLRs/ MyD88,
schimb, agonitii nicotinici s-au dovedit ineficieni p38MAPKs, PI3K/AKT, ERK1/2 (Fig. 5). Aceste
n culturi de monocite de obolan stimulate cu LPS ci de semnalizare necesit o serie de cofactori, n
(56). Nicotina a crescut migraia i chemotaxia ce- aval, care asigur funcionarea cii nicotinice anti-
lulelor stem mezenchimale i celulelor progenitoare inflamatorii.
endoteliale in vitro i a avut efect contrar in vivo Nicotina poate suprima producia de citokine n
(45-49). anumite celule (monocite, macrofage, celule endo-
Efectul supresiv al nicotinei asupra rspunsului teliale, celule epiteliale, celule microgliale) prin in-
imun a fost dovedit n limfocite T (57,59,60). Celu- termediul unui mecanism posttranscripional soldat
lele T exprim majoritatea componentelor sistemu- cu inactivarea cii de semnalizare NFkB. Nicotina
lui colinergic; acetilcolina, colin acetiltransferaza, amelioreaz rspunsul inflamator prin recrutarea
transportor specific pentru colin, colinesteraze, re- IKB, AP-1 sau SOC3 care interacioneaz cu sis-
ceptori muscarinici i nicotinici pentru acetilcolin. temul NFkB. Un alt mecanism de subreglare a cii
REVISTA ROMN DE BOLI INFECIOASE VOLUMUL XVIII, NR. 1, AN 2015 9

JAK2, fosforilarea ulterioar a factorului de trans-


criere STAT3 i activarea cii de semnalizare SOC3
n monocite, sau micro RNA124 i GSK3 n macro-
fage (69-71).
Prin stimularea alfa7nAChR n monocite, ma-
crofage i celule epiteliale cu agoniti TLRs i ago-
niti nicotinici s-a obinut un rspuns antiinflamator
printr-un mecanism mediat de TLRs/MyD88. Inte-
raciunea ligand-receptor a fost urmat de reduce-
rea exprimrii TLR2, TLR3, TLR4, TLR9, CD14 i
subreglarea a numeroase proteine MyD88, TRIF,
IRAK, TARF (72-75). n alte sisteme celulare (ma-
crofage, monocite, feocromocitom, neuroblastom,
PC12), nicotina a stimulat calea de semnalizare
MAPK/ERK (mitogen activated protein kinases/
extracellular signal regulated kinases, denumit i
Ras-Raf-MEK-ERK) (76-78).

CONCLUZII
Exist o serie de date epidemiologice i experi-
mentale pe baza crora se poate aprecia c nicotina
este un alcaloid natural cu proprieti antiinflama-
torii. Potenialul antiinflamator al nicotinei asupra
diferitelor organe i sisteme se realizeaz prin inter-
mediul unor receptori specifici tip alpha7nAChR.
Cercetarea efectelor diferitelor substane agoniste
sau antagoniste ale receptorilor nicotinici n celule
non-neuronale a artat c receptorii nicotinici ho-
mopentamerici alfa7 sunt situai cu precdere n ce-
lule imune i inflamatorii (macrofage, monocite,
neutrofile, mononucleare, trombocite, celule den-
dritice, limfocite B i T, celule NK, celule epiteliale,
FIGURA 5. Semnalizarea alfa7nAChR n boli celule endoteliale, fibroblaste, celule stem hemato-
inflamatorii
poetice, celule stem mezenchimale, celule progeni-
Alpha7nAChR: Homopentaalpha7 subunit nicotinic acetylcholine
receptor; MyD88: Myeloid dierentiation factors 88; TLRs: Toll-like toare endoteliale). Fixarea nicotinei de receptorii
receptors; NFkB: Nuclear factor kappa-light-chain-enhancer of alfa7nAChR iniiaz o serie de evenimente intrace-
activated B cells; JAKs: Janus kinases; STAT: Signal transducer and lulare, mediate de NFkB, JAK/STAT, MyD88/
activator of transcription; PI3K: Phosphatidylinositol 3-kinase;
AKT: Serine/threonine kinase; MAPKs: Mitogen activated protein TLRs, MAPKs/ERKs. Stimularea receptorilor
kinases. alfa7nAChR de la nivelul esuturilor extraneuro-
nale reglementez eliberarea de citokine proinfla-
matorii n circulaia sanguin.
NFkB este reprezentat de creterea AMPc intrace- Efectele antiinflamatorii ale nicotinei asupra di-
lular n urma interaciunii dintre alfa7nAChR i feritelor esuturi sunt greu de interpretat. Se cu-
adenilat ciclaza 6. Aceast cale de transducie pro- noate c stimularea cii nicotinice antiinflamatorii
moveaz fosforilarea CREB, PCREB iniiaz trans- previne eliberarea excesiv a citokinelor i ate-
cripia cfos i inactivarea NFkB. (61,65-68). n nueaz inflamaia local i sistemic. n plus, efec-
limfocite T de oarece, nicotina inactiveaz calea tele acute i cronice ale nicotinei asupra sistemului
de transducie a NFkB prin supresia sintezei Th1 imun sunt, de obicei, opuse. Tratamentul acut cu
(TNF alfa, IFN gamma), a Th17 (IL17, IL17F, nicotin stimuleaz, n timp ce tratamentul cronic
IL22, IL23) i a factorilor de transcripie (RORs, suprim rspunsurile imun i inflamator. n anumite
IkB) (41). modele experimentale, nicotina prezint efecte sti-
n macrofage, nicotina reduce eliberarea citoki- mulante ale receptorilor alfa7nAChR la o anumit
nelor proinflamatorii prin stimularea tirozinkinazei doz i efecte blocante la alte doze. Exist, de
10 REVISTA ROMN DE BOLI INFECIOASE VOLUMUL XVIII, NR. 1, AN 2015

asemenea, interferene farmacologice asupra recep- necesit studii suplimentare i este interesant din
torilor nicotinici ntre nicotina administrat exogen punct de vedere al farmacologiei experimentale.
i acetilcolina endogen.
Interesul terapeutic pentru utilizarea nicotinei ca Not: Aceast lucrare a beneficiat de suport fi-
medicament este astzi limitat din cauza faptului c nanciar prin proiectul CERO profil de carier:
administrarea nicotinei poate promova angiogeneza cercettor romn, contract nr. POSDRU/159/1.5/
i o serie de reacii adverse. Valorificarea potenia- S/135760, proiect cofinanat din Fondul Social
lului terapeutic al nicotinei n combaterea inflama- European prin Programul Operaional Sectorial
iei locale i sistemice din anumite afeciuni umane Dezvoltarea Resurselor Umane 2007-2013.

BIBLIOGRAFIE
1. Jonge W.J., & Ulloa L. (2007). The alpha7 nicotinic acetylcholine 16. Scott D.A., Lamont R.J., Kumar A., Wang H. (2014). Nicotinic
receptor as a pharmacological target for inflammation. British journal augmentation of anti-inflammatory GSK3b signaling. Tobacco
of pharmacology, 151(7), 915-929. Induced Diseases, 12(Suppl 1), A15.
2. Ulloa L. (2005). The vagus nerve and the nicotinic anti-inflammatory 17. Wu, Haiya, Ling Li, Xiao Su. Vagus Nerve through 7 nAChR
pathway. Nature Reviews Drug Discovery, 4(8), 673-684. Modulates Lung Infection and Inflammation: Models, Cells, and
3. Han Y. (2014). Nicotine, an anti-inflammation molecule. Inflammation Signals. BioMed Research International 2014 (2014): 283525. PMC.
and Cell Signaling, 1(4), 10-14800. Web. 17 Dec. 2014.
4. Mabley J., Gordon S., Pacher P. Nicotine exerts an anti- 18. Su X., Jae W.L., Matthay Z.A., et al. Activation of the 7 nAChR
inflammatory effect in a murine model of acute lung injury. reduces acid-induced acute lung injury in mice and rats. American
Inflammation 2011; 34:231-237. Journal of Respiratory Cell and Molecular Biology. 2007; 37(2):186192.
5. Cui W.Y., Zhao S., Polanowska-Grabowska R., Wang J., Wei J., 19. Su X., Matthay M.A., Malik A.B. Requisite role of the cholinergic 7
Dash B., et al. Identification and characterization of poly(I:C)-induced nicotinic acetylcholine receptor pathway in suppressing gram-
molecular responses attenuated by nicotine in mouse macrophages. negative sepsis-induced acute lung inflammatory injury. Journal of
Mol Pharmacol 2013; 83:61-72. Immunology. 2010;184(1):401410.
6. Razani-Boroujerdi S., Boyd R.T., Davila-Garcia M.I., Nandi J.S., 20. Ni Y.F., Tian F., Lu Z.F., et al. Protective effect of nicotine on
Mishra N.C., Singh S.P., et al. T cells express alpha7-nicotinic lipopolysaccharide-induced acute lung injury in mice. Respiration.
acetylcholine receptor subunits that require a functional TCR and 2010; 81(1):3946.
leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ 21. Giebelen I.A.J., van Westerloo D.J., LaRosa G.J., de vos A.F.,
response. J Immunol 2007; 179:2889-2898. van der Poll T. Local stimulation of 7 cholinergic receptors inhibits
7. Scott D.A., & Martin M. (2006). Exploitation of the nicotinic LPS-induced TNF- release in the mouse lung. Shock. 2007;
anti-inflammatory pathway for the treatment of epithelial inflammatory 28(6):700703.
diseases. World Journal of Gastroenterology, 12(46), 7451. 22. Lafargue M., Xu L., Carls M., et al. Stroke-induced activation of
8. Piao W.H., Campagnolo D., Dayao C., Lukas R.J., Wu J., & Shi the 7 nicotinic receptor increases Pseudomonas aeruginosa lung
F.D. (2009). Nicotine and inflammatory neurological disorders. Acta injury. FASEB Journal. 2012; 26(7):29192929.
Pharmacologica Sinica, 30(6), 715-722. 23. Giebelen I.A.J., Leendertse M., Florquin S., van der Poll T.
9. Sadis C., Teske G., Stokman G., Kubjak C., Claessen N., Moore Stimulation of acetylcholine receptors impairs host defence during
F., et al. Nicotine protects kidney from renal ischemia/reperfusion pneumococcal pneumonia. European Respiratory Journal. 2009;
injury through the cholinergic anti-inflammatory pathway. PLoS One 33(2):375381.
2007; 24. Boland C., Collet V., Laterre E., Lecuivre C., Wittebole X., Laterre
10. Chatterjee P.K., Yeboah M.M., Dowling O., Xue X., Powell S.R., P. Electrical vagus nerve stimulation and nicotine effects in
Al-Abed Y., & Metz C.N. (2012). Nicotinic acetylcholine receptor peritonitis-induced acute lung injury in rats. Inflammation. 2011;
agonists attenuate septic acute kidney injury in mice by suppressing 34(1):2935.
inflammation and proteasome activity. PloS one, 7(5), e35361. 25. Brgeon F., Xeridat F., Andreotti N., et al. Activation of nicotinic
11. Agarwal P.K., Van den Born J., Van Goor H., Navis G., Gans R.O., cholinergic receptors prevents ventilator-induced lung injury in rats.
& Bakker S.J. (2012). Renoprotective effects of long-term oral PLoS ONE. 2011; 6(8)e22386
nicotine in a rat model of spontaneous proteinuria. American Journal 26. Kox M., Pompe J.C., Peters E., et al. 7 Nicotinic acetylcholine
of Physiology-Renal Physiology, 302(7), F895-F904. receptor agonist GTS-21 attenuates ventilator-induced tumour
12. Obert D.M., Hua P., Pilkerton M.E., Feng W., & Jaimes E.A. (2011). necrosis factor- production and lung injury. British Journal of
Environmental tobacco smoke furthers progression of diabetic Anaesthesia. 2011; 107(4):559566. .
nephropathy. The American journal of the medical sciences, 341(2), 27. Razani-Boroujerdi S., Singh S.P., Knall C., et al. Chronic nicotine
126. inhibits inflammation and promotes influenza infection. Cellular
Immunology. 2004; 230(1):19.
13. Hayashi S., Hamada T., Zaidi S.F., Oshiro M., Lee J., Yamamoto
28. Grando S. Connection of nicotine to cancer, Nature Reviews Cancer,
T., & Kadowaki, M. (2014). Nicotine suppresses acute colitis and
14, 419-429, 2014.
colonic tumorigenesis associated with chronic colitis in mice.
29. Wang H., Yu M., Ochani M. et al. Nicotinic acetylcholine receptor 7
American Journal of Physiology-Gastrointestinal and Liver
subunit is an essential regulator of inflammation, Nature, vol. 421, no.
Physiology, 307(10), G968-G978.
6921, pp. 384388, 2003.
14. Wu S., Zhao H., Luo H., Xiao Xx., Zhang H., Zuo X. GTS-21, an
30. Su X., Jae W. L., Matthay Z. A. et al. Activation of the 7 nAChR
7-nicotinic acetylcholine receptor agonist, modulates Th1
reduces acid-induced acute lung injury in mice and rats, American
differentiation in CD4+ T cells from patients with rheumatoid arthritis.
Journal of Respiratory Cell and Molecular Biology, vol. 37, no. 2, pp.
Experimental and Therapeutic Medicine, 2014, 8(2), 557562.
186192, 2007.
15. Mathis, Keisa W. Nicotine reduces blood pressure in mouse model
31. Wang H., Liao H., Ochani M. et al. Cholinergic agonists inhibit
of systemic lupus erythematosus. The FASEB Journal, 2013, 27:
HMGB1 release and improve survival in experimental sepsis, Nature
1116.2.
Medicine, vol. 10, no. 11, pp. 12161221, 2004.
REVISTA ROMN DE BOLI INFECIOASE VOLUMUL XVIII, NR. 1, AN 2015 11

32. Su X., Matthay M.A., and Malik A.B. Requisite role of the rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine
cholinergic 7 nicotinic acetylcholine receptor pathway in receptor 7 subunit gene knockout mice, Annals of the Rheumatic
suppressing gram-negative sepsis-induced acute lung inflammatory Diseases, vol. 69, no. 9, pp. 17171723, 2010.
injury, Journal of Immunology, vol. 184, no. 1, pp. 401410, 2010. 51. Rosas-Ballina M., Goldstein R.S., Gallowitsch-Puerta M. et al.
33. Rosas-Ballina M., Goldstein R.S., Gallowitsch-Puerta M. et al. The selective 7 agonist GTS-21 attenuates cytokine production in
The selective 7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for
human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE, Molecular Medicine, vol. 15,
TLR2, TLR3, TLR4, TLR9, and RAGE, Molecular Medicine, vol. 15, no. 7-8, pp. 195202, 2009.
no. 7-8, pp. 195202, 2009. 52. Takahashi H.K., Liu K., Wake H. et al. Effect of nicotine on
34. Takahashi H.K., Liu K., Wake H. et al. Effect of nicotine on advanced glycation end product-induced immune response in human
advanced glycation end product-induced immune response in human monocytes, Journal of Pharmacology and Experimental
monocytes, Journal of Pharmacology and Experimental Therapeutics, vol. 332, no. 3, pp. 10131021, 2010.
Therapeutics, vol. 332, no. 3, pp. 10131021, 2010. 53. Jin H.J., Li H.T., Sui H.X. et al. Nicotine stimulated bone marrow-
35. Huston J.M., Rosas-Ballina M., Xue X. et al. Cholinergic neural derived dendritic cells could augment HBV specific CTL priming by
signals to the spleen down-regulate leukocyte trafficking via CD11b, activating PI3K-Akt pathway, Immunology Letters, vol. 146, no. 1-2,
Journal of Immunology, vol. 183, no. 1, pp. 552559, 2009. pp. 4049, 2012.
36. Su X., Feng X., Terrando N. et al. Dysfunction of inflammation- 54. Reardon C., Duncan G.S., Brstle A. et al. Lymphocyte-derived
resolving pathways is associated with exaggerated postoperative ACh regulates local innate but not adaptive immunity, Proceedings of
cognitive decline in a rat model of the metabolic syndrome, Molecular the National Academy of Sciences of the United States of America,
Medicine, vol. 18, no. 12, pp. 14811490, 2013. vol. 110, no. 4, pp. 14101415, 2013.
37. H.J. Jin, H.T. Li, H.X. Sui et al. Nicotine stimulated bone marrow- 55. Olofsson P.S., Katz D.A., Rosas-Ballina M. et al. 7 nicotinic
derived dendritic cells could augment HBV specific CTL priming by acetylcholine receptor (7nAChR) expression in bone marrow-
activating PI3K-Akt pathway, Immunology Letters, vol. 146, no. 1-2, derived non-T cells is required for the inflammatory reflex, Molecular
pp. 4049, 2012. Medicine, vol. 18, no. 1, pp. 539543, 2012.
38. Reardon C., Duncan G.S., Brstle A. et al. Lymphocyte-derived 56. Su X., Feng X., Terrando N. et al. Dysfunction of inflammation-
ACh regulates local innate but not adaptive immunity, Proceedings of resolving pathways is associated with exaggerated postoperative
the National Academy of Sciences of the United States of America, cognitive decline in a rat model of the metabolic syndrome, Molecular
vol. 110, no. 4, pp. 14101415, 2013. Medicine, vol. 18, no. 12, pp. 14811490, 2013.
39. Olofsson P.S., Katz D.A., Rosas-Ballina M. et al. 7 nicotinic 57. De Rosa R., Garcia A.A., Braschi C., Capsoni S., Maffei L.,
acetylcholine receptor (7nAChR) expression in bone marrow- Berardi N., Cattaneo A. (2005). Intranasal administration of nerve
derived non-T cells is required for the inflammatory reflex, Molecular growth factor (NGF) rescues recognition memory deficits in AD11
Medicine, vol. 18, no. 1, pp. 539543, 2012. anti-NGF transgenic mice. Proceedings of the National Academy of
40. Razani-Boroujerdi S., Boyd R.T., Davila-Garcia M.I., Nandi J.S., Sciences of the United States of America, 102(10), 3811-3816.
Mishra N.C., Singh S.P., et al. T cells express alpha7-nicotinic 58. Hamano R., Takahashi H.K., Iwagaki H., Yoshino T., Nishibori M.,
acetylcholine receptor subunits that require a functional TCR and Tanaka N. Stimulation of alpha7 nicotinic acetylcholine receptor
leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ inhibits CD14 and the toll-like receptor 4 expression in human
response. J Immunol 2007; 179:2889-2898. monocytes. Shock. 2006; 26:358364.
41. Nizri E., Irony-Tur-Sinai M., Faranesh N., Lavon I., Lavi E., 59. Kawashima K., Fujii T. The lymphocytic cholinergic system and its
Weinstock M., & Brenner T. (2008). Suppression of contribution to the regulation of immune activity. Life Sci. 2003;
neuroinflammation and immunomodulation by the 74:675696.
acetylcholinesterase inhibitor rivastigmine. Journal of 60. Skok M., Grailhe R., Agenes F., Changeux J.P. The role of nicotinic
neuroimmunology, 203(1), 12-22. acetylcholine receptors in lymphocyte development. J Neuroimmunol.
42. Yamaguchi H., Friedman H., and Yamamoto Y. Involvement of 2006; 171:8698.
nicotinic acetylcholine receptors in controlling Chlamydia 61. DeRosa M.J., Esandi M.C., Garelli A., Rayes D., Bouzat C.
pneumoniae growth in epithelial HEp-2 cells, Infection and Immunity, Relationship between alpha 7nAChR and apoptosis in human
vol. 71, no. 6, pp. 36453647, 2003. lymphocytes. J Neuroimmunol. 2005; 160:154161.
43. R.W. Saeed, S. Varma, T. Peng-Nemeroff et al. Cholinergic 62. D. Martelli, M.J. McKinley, and R.M. McAllen The cholinergicanti-
stimulation blocks endothelial cell activation and leukocyte inflammatory pathway: a critical review, Autonomic, Neuroscience,
recruitment during inflammation, Journal of Experimental Medicine, vol. 182, pp. 6569, 2014.
vol. 201, no. 7, pp. 11131123, 2005. 63. Gahring L.C., Enioutina E.Y., Myers E.J. et al. Nicotinic receptor 7
44. Pea V.B.A., Bonini I.C., Antollini S.S., Kobayashi T., Barrantes expression identifies a novel hematopoietic progenitor lineage, PLoS
F.J., 7-type acetylcholine receptor localization and its modulation by ONE, vol. 8, no. 3,Article ID e57481, 2013.
nicotine and cholesterol in vascular endothelial cells, Journal of 64. Cloz-Tayarani I., & Changeux J.P. (2007). Nicotine and serotonin
Cellular Biochemistry, vol. 112, no. 11, pp. 32763288, 2011. in immune regulation and inflammatory processes: a perspective.
45. Hoogduijn M.J., Cheng A., Genever P.G. Functional nicotinic and Journal of leukocyte biology, 81(3), 599-606.
muscarinic receptors on mesenchymal stem cells, Stem Cells and 65. Andersson U., Tracey K.J. Neural reflexes in inflammation and
Development, vol. 18, no. 1, pp. 103112, 2009. immunity, Journal of Experimental Medicine, vol. 209, no. 6, pp.
46. Schraufstatter I.U., DiScipio R.G., Khaldoyanidi S.K. Alpha 7 10571068, 2012.
subunit of nAChR regulates migration of human mesenchymal stem 66. Hall S., Kumaria A., Belli A. The role of vagus nerve overactivity in
cells, Journal of Stem Cells, vol. 4, no. 4, pp. 203215, 2009. the increased incidence of pneumonia following traumatic brain
47. Yu M., Liu Q., Sun J., Yi , K, Wu L., and Tan X. Nicotine improves injury, British Journal of Neurosurgery, vol. 28, no. 2, pp. 181186,
the functional activity of late endothelial progenitor cells via nicotinic 2014.
acetylcholine receptors, Biochemistry and Cell Biology, vol. 89, no. 4, 67. Oshikawa J., Toya Y., Fujita T. et al. Nicotinic acetylcholine receptor
pp. 405410, 2011. 7 regulates cAMP signal within lipid rafts, AmericanJournal of
48. Heeschen C., Chang E., Aicher A., and Cooke J.P. Endothelial Physiology: Cell Physiology, vol. 285, no. 3, pp. C567 C574, 2003.
progenitor cells participate in nicotine-mediated angiogenesis, 68. Ray N., Kuwahara M., Takada Y. et al. c-Fos suppresses systemic
Journal of the American College of Cardiology, vol. 48, no. 12, pp. inflammatory response to endotoxin, International Immunology,
25532560, 2006. vol. 18, no. 5, pp. 671677, 2006.
49. Westman M., Engstrm M., Catrina A.I., and Lampa J. Cell 69. Chatterjee P.K., Al-Abed Y., Sherry B., Metz C.N. Cholinergic
specific synovial expression of nicotinic alpha 7 acetylcholine agonists regulate JAK2/STAT3 signaling to suppress endothelial cell
receptor in rheumatoid arthritis and psoriatic arthritis, Scandinavian activation, The American Journal of Physiology Cell Physiology, vol.
Journal of Immunology, vol. 70, no. 2, pp. 136140, 2009. 297, no. 5, pp. C1294C1306, 2009.
50. van Maanenn M.A., Stoof S.P., LaRosa G.J., Vervoordeldonk 70. Pea G., Cai B., Liu J. et al. Unphosphorylated STAT3 modulates
M.J., and Tak P.P. Role of the cholinergic nervous system in alpha7 nicotinic receptor signaling and cytokine production in sepsis,
12 REVISTA ROMN DE BOLI INFECIOASE VOLUMUL XVIII, NR. 1, AN 2015

European Journal of Immunology, vol. 40, no. 9, pp. 25802589, 75. Hamano R., Takahashi H. K., Iwagaki H., Yoshino T., Nishibori M.,
2010. and Tanaka N. Stimulation of 7 nicotinic acetylcholine receptor
71. Sun Y., H. Gui Q. Li, et al. MicroRNA-124 mediates the cholinergic inhibits CD14 and the toll-like receptor 4 expression in human
anti-inflammatory action through inhibiting the production of monocytes, Shock, vol. 26, no. 4, pp. 358364, 2006.
pro-inflammatory cytokines, Cell Research, vol. 23, no. 11, pp. 76. Kihara T., Shimohama S., Sawada H. et al. 7 nicotinic receptor
12701283, 2013. transduces signals to phosphatidylinositol 3-kinase to block A
72. Borovikova L.V., Ivanova S., Zhang M. et al. Vagus nerve beta-amyloid-induced neurotoxicity, The Journal of Biological
stimulation attenuates the systemic inflammatory response to Chemistry, vol. 276, no. 17, pp. 1354113546, 2001.
endotoxin, Nature, vol. 405, no. 6785, pp. 458462, 2000. 77. Gubbins E.J., Gopalakrishnan M., and Li J. 7 nAChR-mediated
73. Wang H., Yu M., Ochani M. et al. Nicotinic acetylcholine receptor 7 activation of MAP kinase pathways in PC12 cells, Brain Research,
subunit is an essential regulator of inflammation, Nature, vol. 421, no. vol. 1328, pp. 111, 2010.
6921, pp. 384388, 2003. 78. Kouhen R.E.L., Hu M., Anderson D.J., Li J., Gopalakrishnan M.
74. Yoshikawa H., Kurokawa M., Ozaki N. et al. Nicotine inhibits the Pharmacology of 7 nicotinic acetylcholine receptor mediated
production of proinflammatory mediators in human monocytes by extracellular signal-regulated kinase signalling in PC12 cells, British
suppression of I-B phosphorylation and nuclear factor-B Journal of Pharmacology, vol. 156, no. 4, pp. 638648, 2009.
transcriptional activity through nicotinic acetylcholine receptor 7,
Clinical and Experimental Immunology, vol. 146, no. 1, pp. 116123,
2006.