Rho-kinase inhibitor attenuates cholestasis-induced CXC chemokine formation, leukocyte recruitment, and hepatocellular damage in the liver.
BACKGROUND
In the present experimental study, we analyzed the role of Rho-kinase during obstructive cholestasis by studying the effect of the Rho-kinase inhibitor Y-27632 on hepatic CXC chemokine formation, leukocyte recruitment and hepatocellular damage.


METHODS
C57BL/6 mice underwent bile duct ligation (BDL) to induce obstructive cholestasis. Mice were pretreated with Y-27632 (1 and 10mg/kg) or the vehicle PBS. Sham-operated animals served as controls. After 12h, hepatic accumulation of leukocytes and sinusoidal perfusion were determined using intravital fluorescence microscopy. Hepatocellular damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). CXC chemokines in the liver were analyzed by ELISA.


RESULTS
Administration of 10mg/kg of Y-27632 protected against cholestasis-induced hepatocellular damage indicated by a more than 87% reduction of ALT and AST in BDL mice. Moreover, this Rho-kinase inhibitor significantly decreased BDL-induced production of CXC chemokines by 44-83% and leukocyte recruitment by 60%. Finally, treatment with Y-27632 restored sinusoidal perfusion in cholestatic animals.


CONCLUSIONS
Our findings indicate that the Rho-kinase signaling pathway plays a key role in the pathophysiology of cholestatic liver injury. Thus, targeting Rho-kinase activity may represent a new therapeutic approach in the treatment of inflammation and liver injury in cholestatic liver diseases.
Laschke
Matthias W
MW
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden. matthias.laschke@uniklinik-saarland.de <matthias.laschke@uniklinik-saarland.de>
Dold
Stefan
S
Jeppsson
Bengt
B
Schilling
Martin K
MK
Menger
Michael D
MD
Thorlacius
Henrik
H
D000410:Alanine Transaminase / Q000097:blood; D000577:Amides / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D019743:Chemokines, CXC / Q000378:metabolism; D002779:Cholestasis / Q000150:complications; D002780:Cholestasis, Intrahepatic / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D000577:Amides; D000959:Antihypertensive Agents; D019743:Chemokines, CXC; D011725:Pyridines; C108830:Y 27632; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D054460:rho-Associated Kinases