Role of nitric oxide in the antifibrotic and anticholestatic actions of interferon-alpha(2b)

Interferons possess important antifibrotic properties. In addition, there i s evidence that they induce the production of nitric oxide (NO) and that it downregulates the synthesis of extracellular matrix by certain cells. The aim of the present work was to evaluate if L-arginine, the NO synthase subs trate, is able to increase the antifibrotic properties of interferon-alpha( 2b) and if L-NAME, an NO synthesis inhibitor, can prevent them. Fibrosis wa s induced by bile duct ligation (BDL) for 5 weeks in rats and interferon-al pha(2b) (IFN; 100,000 IU rat, s.c., daily) and/or L-arginine (500 mg/kg, p. o., twice daily) or L-NAME (100 mg/kg, p.o., twice daily) were administered . Collagen content was determined by measuring hydroxyproline in liver samp les. Malondialdehyde (MDA) was used to estimate lipid peroxidation levels. Glycogen was measured colorimetrically. Serum enzyme activities and bilirub ins were determined by standard procedures. Fibrosis was increased 6-fold b y BDL. L-arginine or IFN partially prevented the increment in collagen. Fur thermore, administration of both drugs simultaneously showed an additive ef fect (P < 0.05), while L-NAME abolished the protective effect of IFN. The s ame effect was observed on the other markers of liver function or damage st udied herein. The additive effects of L-arginine and IFN could be due to a synergism of both compounds by increasing NO concentration, which can act a s an antifibrotic agent but also as a cytoprotective compound. These result s also suggest that the protective effects of IFN are mediated by NO, since L-NAME prevented them. (C) 1999 Wiley-Liss, Inc.