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 common pathway of liver fibrosis. Recently, it has been demonstrated that the small GTPase Rho is involved in HSCs activation, and that Y-27632, an inhibitor of Rho-kinase which is an effector that acts downstream of Rho, inhibits Rho-associated effects. The objective of the current study was to investigate the inhibitory effects of Y-27632 on the activation of HSCs and the progression of liver fibrosis. Methods: Y-27632 (1, 10, 100 muM) was added to HSCs isolated from normal rat liver. Results: HSCs maintained the 'star-like' configuration of the quiescent stage in the presence of Y-27632, as well as inhibition of the expression of Na+/Ca2+ exchanger mRNA which was reported to be an indicator of HSCs activation. 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 serum hyaluronic acid level was reduced. Moreover, Y-27632 reduced the number of smooth muscle alpha -actin-positive cells and transforming growth factor-beta1-positive cells, and inhibited the expression of Na+/Ca2+ exchanger mRNA. Conclusions: These findings indicate that Y-27632 may be useful for the clinical management of liver fibrosis. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.