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
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.
D000199:Actins / Q000096:biosynthesis; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D023421:Models, Animal; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1; D054460:rho-Associated Kinases
D000199:Actins; D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D019831:Sodium-Calcium Exchanger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C108830:Y 27632; D002251:Carbon Tetrachloride; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases