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

• Published in: Journal of hepatology Vol. 30; no. 4; pp. 621 - 631
• Main Authors: Desmoulière, Alexis, Xu, Guoxiong, Costa, Andréa M.A, Yousef, Ibrahim M, Gabbiani, Giulio, Tuchweber, Beatriz
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier B.V 01.04.1999; Elsevier
• Subjects: Acetone - toxicity; Animals; Bile Ducts - physiology; Biological and medical sciences; Carbon Tetrachloride Poisoning - pathology; Cell Differentiation; Cell Division - drug effects; Cells, Cultured; Cholestatic injury; Desmin; Digestive system; Fibroblasts - cytology; Fibroblasts - drug effects; Fibrosis; Hepatic stellate cell; Liver - cytology; Liver - drug effects; Liver - pathology; Liver Cirrhosis, Experimental - chemically induced; Liver Cirrhosis, Experimental - pathology; Male; Medical sciences; Muscle, Smooth - cytology; Muscle, Smooth - drug effects; Myofibroblast; Pentoxifylline - pharmacology; Pharmacology. Drug treatments; Phenotype; Rats; Rats, Sprague-Dawley; α-Smooth muscle actin; Cholestatic injury; Hepatic stellate cell; Myofibroblast; α-Smooth muscle actin; Desmin; Fibrosis; Spider cell; Rat; Pathogenesis; Liver; Cell biology; Hepatic disease; Smooth muscle; Esterases; Phosphoric diester hydrolases; Actin; Modulation; Xanthine derivatives; 3',5'-Cyclic-nucleotide phosphodiesterase; Enzyme; Rodentia; Enzyme inhibitor; Cell differentiation; Pentoxifylline; Vertebrata; Chemotherapy; Experimental disease; Phenotype; Mammalia; Animal; Digestive diseases; Hydrolases
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/S0168-8278(99)80192-5

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 (CCl 4) plus acetone (given twice) or bile duct ligation. Methods: The fibroproliferative response and myofibroblastic phenotypic modulation were evaluated by PCNA and alpha-smooth muscle ( α-SM) actin immunohistochemistry, respectively, in livers taken 24 h after the last CCl 4 treatment or 72 h after bile duct ligation. Desmin expression was also measured, and inflammation was evaluated by ED-1 staining. Furthermore, proliferation and α-SM actin expression were studied in cultured HSCs after pentoxifylline treatment. Results: In the CCl 4-acetone groups, pretreatment with pentoxifylline decreased the proliferative response and expression of α-SM actin in the HSCs. Similarly, pentoxifylline reduced the proliferation and myofibroblastic differentiation of portal fibroblasts after bile duct ligation. Pentoxifylline reduced ED-1 expression, particularly in the CCl 4 model, where there was significant inflammation. In cultured pentoxifylline-treated HSCs, both proliferation and α-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, α-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.