Pentoxifylline prevents fibrosis in an animal model and inhibits platelet-derived growth factor-driven proliferation of fibroblasts.
Liver fibrosis is a complex process characterized by two major events: fibroproliferation and increased collagen synthesis. The exact role of cytokines in the pathogenesis of hepatic fibrosis remains to be established, but platelet-derived growth factor clearly stimulates proliferation of fibroblasts and increases collagen synthesis. In in vitro studies, pentoxifylline, a methylxanthine, significantly reduced platelet-derived growth factor-driven proliferation of fibroblasts. Platelet-derived growth factor has also been identified as a fibroproliferative factor produced spontaneously by monocytes obtained from patients with liver disease. Long-term administration of pentoxifylline (16 mg/kg orally, 5 days/wk for 12 wk) in an animal model of liver fibrosis prevented elevations in gamma-glutamyl transpeptidase and alkaline phosphatase levels and prevented the reduction in serum albumin level normally observed in this animal model of liver disease. The animal model used was a long-term, low-dose yellow phosphorus--induced model in pigs that reproducibly results in extensive fibrosis after 10 to 12 wk of treatment. Long-term administration of pentoxifylline also prevented the histological changes characteristic of fibrosis in this animal model. Collagen concentration was significantly elevated in liver sections obtained from animals receiving yellow phosphorus, compared with controls. Long-term pentoxifylline treatment resulted in significantly lower collagen concentrations in liver sections from animals receiving yellow phosphorus than in sections from animals receiving yellow phosphorus alone; this was supported by histological observation. Therefore administration of pentoxifylline prevented the biochemical and histological changes associated with an animal model of liver disease. Pentoxifylline will likely have an important therapeutic role in liver fibrosis.
Peterson
T C
TC
Dalhousie University, Halifax, Nova Scotia, Canada.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D008099:Liver / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D010431:Pentoxifylline / Q000494:pharmacology*; D010758:Phosphorus / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D012867:Skin / Q000166:cytology*; D005723:gamma-Glutamyltransferase / Q000097:blood
D010982:Platelet-Derived Growth Factor; D010758:Phosphorus; D003094:Collagen; D005723:gamma-Glutamyltransferase; D010431:Pentoxifylline