Therapeutic significance of Y-27632, a Rho-kinase inhibitor, on the established liver fibrosis

Background. Recently, we demonstrated that Y-27632, a Rho-kinase inhibitor, inhibited hepatic stellate cells (HSCs) activation in terms of cellular morphology, improved the progression of carbon tetrachloride (CCl4)-induced rat liver fibrosis. The objective of the present study was to investigate the effects of Y-27632 on the established liver fibrosis. Materials and methods. Liver cirrhosis was induced by intragastric administration of CCl4 once a week for 12 weeks. After the first 6 weeks of CCl4 injection, Y-27632 (30 mg/kg body weight) or saline was continuously administered to the rats via an intraperitoneally implanted osmotic pump during the final 6 weeks of CCl4 injection. Two days after the last CCl4 injection, 70% hepatectomy was performed. Results. Y-27632 prevented the development of CCl4-induced liver fibrosis and improved the fibrotic changes, hydroxyproline content, and serum hyaluronic acid level in the liver. Moreover, Y-27632 reduced the number of smooth muscle alpha-actin- and transforming growth factor beta1-positive cells, and inhibited the expression of Na+/Ca2+ exchanger mRNA which was reported to be an indicator of HSCs activation and liver fibrosis. Further, the Y-27632-treated group showed markedly increased survival rate after hepatectomy. Conclusions. These findings indicated that Y-27632 may be useful therapeutically in liver cirrhosis. (C) 2003 Elsevier Inc. All rights reserved.