Inducible nitric oxide synthase is not essential for the development of fibrosis and liver damage induced by CCl4 in mice

The aim of the present work was to investigate the role of inducible nitric oxide (NO) synthase (iNOS) in CCl(4)-induced cirrhosis by utilizing iNOS knock out mice (iNOS(-/-)). Cirrhosis was produced by i.p. administration of CCl(4) (1 ml kg(-1) of body weight) dissolved in olive oil three times a week for 3 months to iNOS(-/-) or iNOS(+/+) (wild type) mice; appropriate olive oil controls were performed. Nitrite plus nitrate levels were lower in iNOS(-/-) compared with iNOS(+/+) mice, but CCl(4) did not produce a significant effect in any mice. Reduced (GSH) glutathione was increased in iNOS(-/-) mice receiving vehicle and in both groups receiving CCl(4); lipid peroxidation increased significantly in iNOS(+/+) but not in iNOS(-/-) mice. Bilirubins, alanine aminotransferase and collagen (measured as the hepatic hydroxyproline content) were increased significantly by the chronic intoxication with CCl(4) in both iNOS(-/-) and iNOS(+/+) mice; importantly there was no difference between these groups. This study clearly suggests that NO derived from iNOS does not participate in cholestasis, necrosis or fibrosis induced by CCl(4) in the mice. The present results are in disagreement with several studies indicating a beneficial or detrimental effect of this molecule utilizing different experimental approaches and in agreement with some studies indicating that NO does not affect liver damage in some models. It must be pointed out that this is the first report in iNOS knock out mice utilizing the chronic model of intoxication with CCl(4); thus, comparisons with other models or approaches are difficult to reconcile.