BILIARY DISEASE Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis
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چکیده
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.
منابع مشابه
Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis.
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 m...
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BACKGROUND Non-alcoholic steatohepatitis (NASH) is a metabolic disorder of the liver, which may evolve to fibrosis or cirrhosis. Pentoxifylline (PTX) has been postulated to act as an antifibrogenic agent able to inhibit hepatic stellate cell proliferation and collagen synthesis in vitro. Short-term studies suggest beneficial effects of PTX in experimental models of NASH. AIM To study whether ...
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