Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells

Background/Aims: Activation of hepatic stellate cells (HSCs) is a final com mon pathway of liver fibrosis. Recently, it has been demonstrated that the small GTPase Rho is involved in HSCs activation, and that Y-27632, an inhib itor of Rho-kinase which is an effector that acts downstream of Rho, inhibi ts Rho-associated effects. The objective of the current study was to invest igate the inhibitory effects of Y-27632 on the activation of HSCs and the p rogression of liver fibrosis. Methods: Y-27632 (1, 10, 100 muM) was added to HSCs isolated from normal ra t liver. Results: HSCs maintained the 'star-like' configuration of the quiescent sta ge in the presence of Y-27632, as well as inhibition of the expression of N a+/Ca2+ exchanger mRNA which was reported to be an indicator of HSCs activa tion. In addition, when Y-27632 (30 mg/kg body weight) was administered to rats with carbon tetrachloride-induced liver fibrosis, collagen deposition was inhibited, the hepatic hydroxyproline content was decreased, and the se rum hyaluronic acid level was reduced. Moreover, Y-27632 reduced the number of smooth muscle alpha -actin-positive cells and transforming growth facto r-beta1-positive cells, and inhibited the expression of Na+/Ca2+ exchanger mRNA. Conclusions: These findings indicate that Y-27632 may be useful for the cli nical management of liver fibrosis. (C) 2001 European Association for the S tudy of the Liver. Published by Elsevier Science B.V. All rights reserved.