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 (CCl(4))-induced rat liver fibrosis. The objective of the present study was to investigate the effects of Y-27632 on the established liver fibrosis. METHODS AND METHODS: Liver cirrhosis was induced by intragastric administration of CCl(4) once a week for 12 weeks. After the first 6 weeks of CCl(4) 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 CCl(4) injection. Two days after the last CCl(4) injection, 70% hepatectomy was performed. RESULTS: Y-27632 prevented the development of CCl(4)-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(+)/Ca(2+) 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.