Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis

Abstract

Background: The trisubstituted methylxanthine derivative pentoxifylline inhibits hepatic stellate cell proliferation and collagen synthesis in vitro. The antifibrotic effect of pentoxifylline in a suitable in vivo model of chronic liver fibrogenesis remains to be tested. Methods: Groups of adult rats (n=20-23) received oral pentoxifylline at a dose of 8 mg/kg/day from week 1 to week 6, and 16 mg/kg/day from week 1 to week 6 or week 4 to week 6 after complete bile duct occlusion. Animals who underwent sham operation that received 16 mg/kg/day pentoxifylline and untreated rats with bile duct occlusion alone served as controls. After six weeks, animals were sacrificed and parameters of fibrogenesis determined. Results: Bile duct occlusion caused portal cirrhosis with a 10-fold increased hepatic collagen content in the absence of inflammation or necrosis. This was accompanied by an 11-fold elevated serum aminoterminal procollagen III peptide (PIIINP). The drug induced a dramatic eightfold downregulation of procollagen I mRNA, and suppression of the fibrogenic factors transforming growth factor β1 and connective tissue growth factor by 60-70%. However, profibrogenic tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA was increased twofold, resulting in only a moderate decrease in liver collagen, fibrosis score, and PIIINP. Conclusions: We conclude that targeting pentoxifylline to the fibrogenic cells, thereby avoiding upregulation of TIMP-1, could become a potent antifibrogenic tool in chronic liver disease.