Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells.
OBJECTIVE
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.
Murata
T
T
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Japan. tmura@kuhp.kyoto-u.ac.jp
Arii
S
S
Nakamura
T
T
Mori
A
A
Kaido
T
T
Furuyama
H
H
Furumoto
K
K
Nakao
T
T
Isobe
N
N
Imamura
M
M
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D012333:RNA, Messenger; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases