POSSIBLE ANTIFIBROTIC EFFECTS of FENOFIBRATE a PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR- AGONIST ALONE or COMBINED with PENTOXIFYLLINE in CONCANAVALIN A- INDUCED CHRONIC HEPATITIS in RATS

Abstract

Background&aim: Peroxisome proliferator-activated receptor-α (PPARα) are physiologically highly expressed by hepatocytes, where they play a pivotal anti-inflammatory and metabolic role. The decreased expression and functional activity of PPARα in hepatocytes and increased TNF- α level during hepatitis C virus infection may contribute to the pathogenesis of diseases in humans. This study aims at evaluating the effects of PPARα activation with fenofibrate (FF) and TNF- α inhibition with pentoxifylline (PTX) either as a monotherapy or in combination on liver inflammation, fibrosis and portal pressure (PP) in concanavalin A (Con A)- induced chronic hepatitis in rats. Methods: The rats were randomly divided to 5 groups; control group recieved (1ml saline iv/wk), con A treated group recieved (20mg/kg .iv/wk), Con A+ FF pretreated group recieved (100 mg/kg/day p.o), Con A +PTX preteated group recieved (200 mg/kg/day p.o) and (Con A+FF-PTX) pretreated group with the above doses. Measurement of PP was performed by the end of the 8th week. Blood samples and livers were collected at the end of the 1st, 2nd, 4thand 8th weeks for biochemical, histopathological and immunohistochemistry studies for α-smooth muscle actins (α SMA). Results: FF and PTX pretreated groups produced significant (p<0.05) decrease in PP and serum ALT, AST, hepatic TNF α and MDA compared to Con A treated group. Histopathological examination revealed that FF pretreatment started early to improve the histopathological and immunohistochemical studies (anti-inflammatory, anti-fibrogenic effects through suppressing HSC activation, and apoptosis of nonparenchymal cells) in comparison to PTX pretreatment. On the other hand, chronic pretreatment with FF and PTX as combination did not add a significant additive beneficial effect. In conclusion: FF or PTX as a monotherapy significantly reduced PP, liver inflammation and fibrosis in Con A model of chronic hepatitis that may represent a new therapeutic strategy for hepatitis and its complications and the combination of both drugs did not add an additive beneficial effect. Key words: PPARα; fenofibrate; pentoxifylline; concanavalin A; portal pressure; Malondialdehyde; tumor necrosis factor alpha.