Reduction of hepatic ischemia/reperfusion-induced injury by a specific ROCK/Rho kinase inhibitor Y-27632
Reduction of hepatic ischemia/reperfusion-induced injury by a specific ROCK/Rho kinase inhibitor Y-27632
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DOI：
10.1016/s0022-4804(02)00081-1
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发表时间：
2003-02-01
影响因子：
2.2
通讯作者：
Yamaoka, Y
中科院分区：
文献类型：
--
作者：
Ikeda, F;Terajima, H;Yamaoka, Y
背景已知低分子量GTdR Rho通过激活几种下游效应物而充当分子开关，其中之一是Rho相关卷曲螺旋形成蛋白激酶（ROCK）。ROCK/Rho激酶介导细胞因子依赖性细胞功能，如基于肌动蛋白的平滑肌收缩和整合素介导的细胞粘附。最近开发了ROCK/Rho激酶的特异性抑制剂Y-27632。本研究检测了Y-27632是否可以通过减弱微循环障碍对肝缺血/再灌注（I/R）诱导的损伤提供有益的作用。在雄性Sprague-Dawley大鼠中，通过将肝蒂夹在左叶和中叶90分钟，然后再灌注2小时来诱导常温部分缺血。在治疗组中，Y-27632在缺血性损伤之前静脉内给药。用活体荧光显微镜观察肝脏微循环。观察肝酶释放情况及肝组织病理学变化。Y-27632显著改善了肝窦灌注，减少了粘附在肝窦和肝窦后小静脉中的白细胞数量。血窦和窦后小静脉的缺血后狭窄也被明显抑制。因此，肝酶释放减少，缺血后组织学损伤被抑制。特异性ROCK/Rho激酶抑制剂Y-27632可通过改善缺血后微循环来减轻肝脏I/R诱导的损伤。Y-27632的给药可能是克服肝脏I/R诱导的损伤的新策略。(C)2003 Elsevier Science（美国）。
Background. The low-molecular-weight GTPase Rho is known to act as a molecular switch by activating several downstream effectors, one of which is Rho-associated coiled-coil forming protein kinase (ROCK). ROCK/Rho kinase mediates cytoskeleton-dependent cell functions, such as actomyosin-based smooth muscle contraction and integrin-mediated cell adhesion. A specific inhibitor of ROCK/Rho kinase, Y-27632, was recently developed. The present study examined whether Y-27632 could provide a beneficial effect on hepatic ischemia/reperfusion (I/R)-induced injury through the attenuation of microcirculatory disturbance.Materials and methods. In male Sprague-Dawley rats, normothermic partial ischemia was induced by clamping the hepatic pedicle to the left and median lobes for 90 min, followed by 2 h of reperfusion. In the treatment group, Y-27632 was intravenously administered prior to ischemic insult. Hepatic microcirculation was investigated by using intravital fluorescence microscopy. Liver enzyme release and histological changes of the liver tissue were also evaluated.Results. Y-27632 significantly improved sinusoidal perfusion and reduced the number of leukocytes sticking in hepatic sinusoids and adhering in postsinusoidal venules. The postischemic narrowing of both sinusoids and postsinusoidal venules was also markedly suppressed. Consequently, liver enzyme release was reduced and postischemic histological damage was suppressed.Conclusions. A specific ROCK/Rho kinase inhibitor, Y-27632, was useful to alleviate hepatic I/R-induced injury through ameliorating postischemic microcirculation. The administration of Y-27632 may be a novel strategy for conquering hepatic I/R-induced injury. (C) 2003 Elsevier Science (USA).