Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis. Issue 2 (1st February 2002)

• Record Type: Journal Article
• Authors: Raetsch, C; Jia, J D; Boigk, G; Bauer, M; Hahn, E G; Riecken, E-O; Schuppan, D
• Is Part Of: Gut. Volume 50:Issue 2(2002)
• Page Start: 241
• Page End: 247
• Publication Date: 2002-02-01
• Subjects: antifibrotics -- pentoxifylline -- cirrhosis -- connective tissue growth factor; ALT, alanine aminotransferase -- ALP, alkaline phosphatase -- AST, aspartate aminotransferase -- BDO, bile duct occlusion -- cAMP, cyclic adenosine monophosphate -- CTGF, connective tissue growth factor -- GAPDH, glyceraldehyde-3-phosphate dehydrogenase -- γGT, gamma glutamyl transpeptidase -- HYP, hydroxyproline -- PCR, polymerase chain reaction -- PDE, phosphodiesterase -- PTX, pentoxifylline -- PIIINP, (serum) aminoterminal propeptide of procollagen type III -- TGF-β, transforming growth factor β -- TIMP-1, tissue inhibitor of metalloproteinase 1; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.50.2.241
• Languages: English
• ISSNs: 0017-5749

Abstract

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.