Increased oxidative stress in dimethylnitrosamine-induced liver fibrosis in the rat: effect of N-acetylcysteine and interferon-alpha.
Oxidative stress may represent a common link between chronic liver damage and hepatic fibrosis. Antioxidants and interferon seem to protect against hepatic stellate cell (HSC) activation and liver fibrosis. This study evaluated (1) the effect of the profibrotic agent dimethylnitrosamine (DMN) on the hepatic oxidative balance in the rat; (2) the role played by the antioxidant agent N-acetylcysteine (NAC); and (3) the antifibrotic effects of two different types of interferon-alpha: recombinant alpha-2b (rIFN-alpha) and leukocyte alpha (LeIFN-alpha). Five groups of rats received: (1) saline; (2) DMN; (3) DMN + NAC; (4) DMN + rIFN-alpha; and (5) DMN + LeIFN-alpha. Oxidative balance was evaluated by hepatic glutathione, TBARs, protein carbonyl, and sulfhydryl determination. Fibrosis was determined by hepatic hydroxyproline content and fibronectin (FN) staining (immunohistochemistry). DMN rats showed a diffuse FN deposition, an impaired oxidative balance, and higher hepatic hydroxyproline levels compared to that of controls. NAC administration significantly reduced FN deposition, increased hepatic glutathione, and decreased TBARs and protein carbonyls. Administration of IFN-alpha exerted different effects according to the type used. Both IFNs decreased FN deposition; however, LeIFN-alpha significantly improved histology and oxidative parameters compared to those of untreated DMN and rats treated with rIFN-alpha. This study shows the role of free radicals in this model of hepatic fibrosis; the protective effect of NAC against liver fibrosis; and the antifibrotic effect exerted by IFN-alpha (particularly LeIFN-alpha) independent of its antiviral activity.
Vendemiale
G
G
Department of Internal and Public Medicine (DIMIMP), University of Bari, Bari, Italy. g.vendemiale@semeiotica.uniba.it
Grattagliano
I
I
Caruso
M L
ML
Serviddio
G
G
Valentini
A M
AM
Pirrelli
M
M
Altomare
E
E
D000111:Acetylcysteine / Q000627:therapeutic use; D000818:Animals; D004128:Dimethylnitrosamine / Q000633:toxicity*; D016166:Free Radical Scavengers / Q000627:therapeutic use; D016898:Interferon-alpha / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D016166:Free Radical Scavengers; D016898:Interferon-alpha; D017392:Thiobarbituric Acid Reactive Substances; D004128:Dimethylnitrosamine; D000111:Acetylcysteine