Prevention of ischemia–reperfusion-induced hepatic microcirculatory disruption by inhibiting stellate cell contraction using rock inhibitor1
Prevention of ischemia–reperfusion-induced hepatic microcirculatory disruption by inhibiting stellate cell contraction using rock inhibitor1
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通过使用岩石抑制剂抑制星状细胞收缩来预防缺血再灌注引起的肝脏微循环破坏1
作者：
K. Mizunuma;H. Ohdan;H. Tashiro;Y. Fudaba;Hisao Ito;T. Asahara
背景。我们证明，与来自完整大鼠肝脏的 HSC 相比，从暴露于热缺血的大鼠肝脏中分离的肝星状细胞 (HSC) 具有显着的收缩性。这表明缺血再灌注 (IR) 引起的正弦微循环损伤至少部分是由 HSC 收缩引起的。方法。 Rho 相关卷曲螺旋形成蛋白丝氨酸/苏氨酸激酶 (ROCK) 是 HSC 运动的关键调节因子之一。因此，我们研究了 p160ROCK 特异性抑制剂 Y-27632 在体内大鼠部分肝 IR 模型和大鼠原位肝移植模型中是否对热 IR 损伤具有有益作用。结果。热缺血 90 分钟再灌注后，未经治疗的对照大鼠的肝脏持续充血，线粒体呼吸受损，体内近红外光谱显示肝组织中脱氧血红蛋白增加和细胞色素氧化酶含量减少。再灌注1小时后，这些大鼠的血清转氨酶和内皮素(ET)-1水平显着升高。相反，当口服 Y-27632（3-30 mg/kg）时，肝组织中脱氧血红蛋白和细胞色素氧化酶的含量迅速恢复正常。在这些动物中，血清转氨酶水平的升高，但ET-1水平的升高，被显着抑制。这与体外数据一致，表明即使在 ET-1 存在的情况下，Y-27632 也会导致 HSC 松弛。此外，在大鼠原位肝移植模型中，Y-27632预处理显着提高了接受45分钟热缺血的肝移植受者的存活率。结论。 Y-27632 通过抑制 HSC 收缩来减轻 IR 诱导的肝脏微循环破坏。
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.
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内皮素 1 和内皮素 3 在大鼠肝脏中的血管和靶细胞特异性作用。
DOI：
10.1152/ajpgi.1995.269.2.g269
发表时间：
1995
期刊：
The American journal of physiology
影响因子：
--
作者：
Zhang,JX;Bauer,M;Clemens,MG
通讯作者：
Clemens,MG
影响因子：
15.9
作者：
ROCKEY, DC;HOUSSET, CN;FRIEDMAN, SL
通讯作者：
FRIEDMAN, SL
内皮素可增加 α 毒素透化兔肠系膜动脉中肌丝 Ca2+ 的敏感性。
影响因子：
20.1
作者：
Nishimura,J;Moreland,S;Ahn,HY;Kawase,T;Moreland,RS;vanBreemen,C
通讯作者：
vanBreemen,C
DOI：
10.1073/pnas.93.3.1340
发表时间：
1996-02-06
影响因子：
11.1
作者：
Gong, MC;Iizuka, K;Somlyo, AP
通讯作者：
Somlyo, AP
影响因子：
6.2
作者：
Pei, Zhong;Pang, Hao;Block, Michelle L.
通讯作者：
Block, Michelle L.