Effect of Pentoxifylline on Liver Fibrosis and Cell Cycle Related Proteins in Thioacetamide-Induced Rat Cirrhosis

Jang, Kee Taek; Lee, Mee Suk; Jung, In Pyung; Kim, Mee Ran; Jang, Ja June

Abstract

Background: Thioacetamide is a classic hepatotoxic reagent which leads to the reproducible hepatic fibrosis in rats. Thioacetamide-induced fibrosis is an appropriate model for cirrhosis in humans due to the long duration of course and similiar histology. Thioacetamide produces hepatotoxicity through lipid peroxidation but it is unclear whether lipid peroxidation directly correlated with hepatic fibrosis. Pentoxifylline, a derivative of the methylxanthine, showed an antifibrogenic effect in cell cultures of human fibroblasts and some animal models. But this antifibrogenic effect is controversial. Pentoxifylline revealed a hepatoprotective effect in some toxic hepatitis. This hepatoprotective effect seems to influence cell cycle regulatory protein during regeneration. This study aimed to evaluate an effect of pentoxifylline on fibrosis and cell cycle regulatory protein during liver regeneration in thioacetamide-induced rat cirrhosis. Lipid peroxidation assay was compared with collagen content so as to evaluate the correlation with fibrosis. METHOD: Liver cirrhosis was induced by 0.03% oral administration of thioacetamide. Pentoxifylline was administered simultaneously with thioacetamide. The semiquantitative fibrosis index was measured based on histologic finding. Collagen content was estimated by spectrophotometric assay. Activated hepatic stellate cells were counted using alpha-SMA immunohistochemistry. Malondialdehyde, lipid peroxidation metabolite, was estimated by thiobarbituric acid reactive substance assay. Cell cycle regulatory protein was evaluated by western blot.
RESULTS
There was no difference in semiquantitative fibrosis index, collagen content and hepatic stellate cell count between thioacetamide treated rats and simultaneous pentoxifylline treated rats. Lipid peroxidation product was not correlated with collagen content. Western blot showed no difference in cell cycle regulatory protein.
CONCLUSION
Pentoxifylline does not show an antifibrogenic effect in thioacetamide-induced rat cirrhosis, in which thioacetamide induced hepatocellular damage and fibrosis. Lipid peroxidation may be a secondary effect rather than primary mediating mechanism in hepatic fibrosis.