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 microM) 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.
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 microM) 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.
Authors: Seema S Desai; Jason C Tung; Vivian X Zhou; James P Grenert; Yann Malato; Milad Rezvani; Regina Español-Suñer; Holger Willenbring; Valerie M Weaver; Tammy T Chang Journal: Hepatology Date: 2016-03-09 Impact factor: 17.425
Authors: Muhammad A Sohail; Ardeshir Z Hashmi; Wyel Hakim; Azuma Watanabe; Alexander Zipprich; Roberto J Groszmann; Jonathan A Dranoff; Natalie J Torok; Wajahat Z Mehal Journal: Hepatology Date: 2009-01 Impact factor: 17.425