S-nitroso-N-acetylcysteine attenuates liver fibrosis in cirrhotic rats.
This study was aimed to investigate the molecular mechanisms underlying prevention of hepatic fibrosis by S-nitroso-N-acetylcysteine (SNAC), a nitric oxide donor that inhibits lipid peroxidation. Secondary biliary cirrhosis was induced by 4 weeks of common bile duct ligation (CBDL). Both sham-operated and CBDL animals received SNAC (6.0 micromol/kg/day) starting 2 weeks after surgery. SNAC treatment reduced the increase in blood enzyme activities (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), induced by CBDL. Histological changes were attenuated and there was a significant decrease in the area of liver fibrosis and in the activation of stellate cells measured by alpha-smooth muscle actin (alpha-SMA) immunostaining. The increase in TBARS concentration and hydroperoxide-induced chemiluminescence were also reduced by SNAC treatment. SNAC down-regulated expression of collagen 1 alpha, alpha-SMA, tumor necrosis factor-alpha, tumor growth factor-beta, metalloproteinase-2, metalloproteinase inhibitor 1, platelet-derived growth factor (PDGF), and PDGF receptor in CBDL rats. These effects were accompanied by inhibited activation of extracellular signal-regulated kinases, Jun amino-terminal kinases, p38 and Akt. Antifibrotic effects were more efficient than those of the free thiol NAC administered at a dose of 60 mumol/kg. In conclusion, results obtained indicate that SNAC, beyond its antioxidant capacity, exerts antifibrotic effects in rats with secondary biliary cirrhosis by down-regulating increased expression of genes and modulating intracellular signaling pathways that contribute to the accumulation of matrix proteins. Thus, SNAC may be an interesting candidate for the treatment of human fibrosis and cirrhosis.
Vercelino
Rafael
R
Laboratory of Experimental Hepatology and Physiology, Porto Alegre Clinical Hospital, Federal University of Rio Grande do Sul, UFRGS, 90035-903, Ramiro Barcelos, 2350, Porto Alegre, RS, Brazil.
Crespo
Irene
I
de Souza
Gabriela F P
GF
Cuevas
Maria Jose
MJ
de Oliveira
Marcelo G
MG
Marroni
Norma Possa
NP
González-Gallego
Javier
J
Tuñón
María Jesús
MJ
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology*; D007150:Immunohistochemistry / Q000379:methods; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000628:therapy; D020935:MAP Kinase Signaling System; D008297:Male; D009569:Nitric Oxide / Q000737:chemistry; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism
D000975:Antioxidants; D009569:Nitric Oxide; C024940:S-nitroso-N-acetylcysteine; D013482:Superoxide Dismutase; D000111:Acetylcysteine