Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation

Abstract

Hepatic fibrosis or increased liver collagen contents drive functional abnormalities that, when extensive, may be life threatening. The purpose of this study was to assess the effects of the chronic stimulation or inhibition of nitric oxide synthesis in rats with hepatic fibrosis induced by permanent common bile duct ligation (3 weeks) and the role of expression of the different nitric oxide synthase isoforms. Bile duct ligation led to an important accumulation of collagen in the hepatic parenchyma, as shown both histologically and by the hydroxyproline contents of livers. Bilirubin and serum enzyme activities (measured as markers of cholestasis) increased several-fold after bile duct ligation. The area of fibrotic tissue, liver hydroxyproline content and serum markers of cholestasis were clearly related in obstructed rats. The absence of modifications in haemodynamic parameters excludes circulatory changes from being responsible for the development of liver alterations. In animals treated with NG-nitro-L-arginine methyl ester (L-NAME) the area of fibrosis was similar to that of untreated animals, the signs of cholestasis and cellular injury being more evident. In rats treated with L-arginine the area of fibrosis was almost three times larger than that found in bile duct ligated rats and in L-NAME-treated bile duct ligated rats, although the observed biochemical changes were similar to those seen in rats treated with L-NAME. Our results with inducible nitric oxide synthase, obtained by Western blots and immunohistochemistry, indicate a greater expression of the inducible enzyme in bile duct ligated and L-arginine-treated animals and a lower expression in the L-NAME and control groups. Constitutive nitric oxide synthase expression, obtained by Western blots, was very similar in all groups, except for the L-arginine-treated rats in which it was lower. These results suggest that nitric oxide production may be a key factor in the development of fibrosis in bile duct ligated rats. They also support the hypothesis of a dual role for nitric oxide; one beneficial, mediated by its circulatory effects, and the second negative, through its local toxic effects.

The role of iNOS in cholesterol-induced liver fibrosis

“…Data from animal models of fibrosis or NASH-related liver fibrosis have shown conflicting results of both beneficial and deleterious effects of iNOS. [12][13][14][15][16][17][18][19] The exact reason/s for these paradoxical effects is difficult to explain. Therefore, the present study was undertaken to elucidate the role of iNOS in the pathophysiology of liver fibrosis due to consumption of a HCD.…”

Effect of tenoxicam on rat liver tissue

“…Inducible nitric oxide synthase (iNOS) expression was also shown to be present in healthy individuals; however, the amount of expression increases under certain conditions such as cirrhosis (33,34). The high levels of hepatic NO are related with hepatotoxicity (35).…”

Endoglin Upregulation in the Liver after Bile Duct Ligation in Rats

“…Granada. Spain) whose application to assess liver fibrosis has been previously described by us [38]. A total of 15 images of each liver slide were captured and processed.…”

“…and the concentration of total bilirrubin in plasma were determined by standard auto-analyser methods on a CIBA CORNING 550 Express. Liver hydroxyproline determinations were performed as previously described by us [38].…”