Prevention of ischemia-reperfusion-induced hepatic microcirculatory disruption by inhibiting stellate cell contraction using rock inhibitor.
BACKGROUND
We demonstrated that hepatic stellate cells (HSCs) isolated from rat livers exposed to warm ischemia are significantly contractile when compared with HSCs from intact rat livers. This suggests that ischemia-reperfusion (IR)-induced impairment of sinusoidal microcirculation results, at least in part, from contraction of HSCs.


METHODS
Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) is one of the key regulators of HSCs motility. Therefore we investigated whether Y-27632, a p160ROCK-specific inhibitor, has beneficial effects on warm IR injury in an in vivo rat partial liver IR model and a rat orthotopic liver transplantation model.


RESULTS
After reperfusion following 90 min of warm ischemia, livers in untreated control rats had persistent congestion and impaired mitochondrial respiration, as demonstrated by increasing deoxy-hemoglobin and reduced cytochrome oxidase contents in the hepatic tissues using in vivo near-infrared spectroscopy. Serum levels of transaminase and endothelin (ET)-1 in these rats were markedly increased 1 hr after reperfusion. In contrast, when Y-27632 (3-30 mg/kg) was administered orally, hepatic tissue contents of deoxy-hemoglobin and cytochrome oxidase rapidly normalized. In such animals, the elevation of serum transaminase levels, but not that of ET-1 levels, was significantly suppressed. This is consistent with in vitro data demonstrating that Y-27632 causes HSCs to undergo relaxation even in the presence of ET-1. Moreover, in a rat orthotopic liver transplantation model, Y-27632 pretreatment dramatically improved the survival of recipients with liver grafts subjected to 45 min of warm ischemia.


CONCLUSIONS
Y-27632 attenuates IR-induced hepatic microcirculation disruption by inhibiting contraction of HSCs.
Mizunuma
Kazuyuki
K
Second Department of Surgery, Hiroshima University, Faculty of Medicine, Hiroshima, Japan.
Ohdan
Hideki
H
Tashiro
Hirotaka
H
Fudaba
Yasuhiro
Y
Ito
Hisao
H
Asahara
Toshimasa
T
D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004798:Enzymes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007511:Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008102:Liver Circulation / Q000187:drug effects*; D017093:Liver Failure / Q000517:prevention & control; D016031:Liver Transplantation; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008930:Mitochondria, Liver / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology*; D054460:rho-Associated Kinases
D000577:Amides; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D004798:Enzymes; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases