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

J Hepatol. 2001 Oct;35(4):474-81. doi: 10.1016/s0168-8278(01)00169-6.

Abstract

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.

MeSH terms

  • Amides / pharmacology*
  • Animals
  • Disease Progression
  • Enzyme Inhibitors / pharmacology*
  • Homeodomain Proteins / genetics
  • Intracellular Signaling Peptides and Proteins
  • Liver / drug effects*
  • Liver / pathology
  • Liver / physiopathology*
  • Liver Cirrhosis / pathology*
  • Liver Cirrhosis / physiopathology*
  • Male
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Pyridines / pharmacology*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • rho-Associated Kinases

Substances

  • Amides
  • Enzyme Inhibitors
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • Pyridines
  • RNA, Messenger
  • Y 27632
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases