Article Text
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.
- 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