Effect of pentoxifylline on early proliferation and phenotypic modulation of fibrogenic cells in two rat models of liver fibrosis and on cultured hepatic stellate cells

Background/Aims: During liver fibrosis, different fibroblastic cells, i.e. hepatic stellate cells (HSCs) or portal fibroblasts, are involved in the development of lesions, and acquire myofibroblastic differentiation. We investigated, in the rat, whether pentoxifylline can influence the early phase of fibrogenesis in two animal models of fibrosis induced by either carbon tetrachloride (CCl4) plus acetone (given twice) or bile duct ligation. Methods: The fibroproliferative response and myofibroblastic phenotypic modulation were evaluated by PCNA and alpha-smooth muscle (alpha-SM) actin immunohistochemistry, respectively, in livers taken 24 h after the last CCl4 treatment or 72 h after bile duct ligation, Desmin expression was also measured, and inflammation was evaluated by ED-1 staining. Furthermore, proliferation and alpha-SM actin expression were studied in cultured HSCs after pentoxifylline treatment. Results: In the CCl4-acetone groups, pretreatment with pentoxifylline decreased the proliferative response and expression of alpha-SM actin in the HSCs. Similarly pentoxifylline reduced the proliferation and myofibroblastic differentiation of port al fibroblasts after bile duct ligation. Pentoxifylline reduced ED-1 expression, particularly in the CCl4 model, where there was significant inflammation. In cultured pentoxifylline-treated HSCs, both proliferation and alpha-SM actin expression were decreased. Conclusions: In both animal models of fibrosis, during the early stages of tissue injury, pentoxifylline was able to reduce fibroproliferation and myofibroblastic differentiation and to reduce hepatocellular damage and the inflammatory response, particularly in the toxin-induced model. In culture, alpha-SM actin expression decreased in both growing and quiescent HSCs treated with pentoxifylline, indicating that the drug may also exert a direct effect on hepatic fibrogenic cells.