Strategy for Liver Failure by Regulating Hepatic Microcirculation through Hepatic Stellate Cell Activatity

肝星状细胞通过收缩和松弛来调节肝窦血流。当它被激活收缩时，正弦血流量减少。因此，认为调节肝星状细胞的激活可能是改善肝脏微循环的潜在策略。在TAA诱导的大鼠肝硬变模型上，我们阐明了N-乙酰-L半胱氨酸(NAC)对肝星状细胞的激活和纤维化的进展有很强的预防作用。在这种模型中，微循环得到了很好的维持。ROCK/Rho激酶抑制剂Y-27632也被认为可以防止肝星状细胞的激活和防止纤维化。在这一系列研究中，我们考察了Y-27632是否具有改善肝脏微循环的作用。在大鼠肝脏缺血再灌流模型上，我们用半侧夹夹法对其进行了研究。活体显微镜观察显示，Y-27632通过明显改善肝脏微循环，对缺血再灌流所致的肝脏损伤具有保护作用。与假手术组比较，肝窦及肝窦后小静脉直径、肝窦血流灌注率维持不变。血窦和血窦后小静脉内白细胞黏附较少，对血液流动障碍也有保护作用。Y-27632还能改善内毒素血症所致的微循环障碍。

Hepatic stellate cell is known to regulate hepatic sinusoidal blood flow through its contraction and relaxation. When it is contracted by activation, sinusoidal blood flow is reduced. Therefore, it is considered that regulation of activation of hepatic stellate cell can be a potential strategy to improve hepatic microcirculation. We have clarified in TAA-induced cirrhosis model of rats that N-acetyl-L-cysteine (NAC) has a powerful effect on prevention of hepatic stellate cell activation and progress of fibrosis. In such model, microcirculation was well maintained. Rock/Rho kinase inhibitor, Y-27632 is also known to prevent activation of hepatic stellate cell and prevent fibrosis. In this series of the study, we have examined whether Y-27632 has an effect on improvement of hepatic microcirculation. We have investigated it in ischemia/reperfusion model of rat liver using hemHateral clamp of the.liver. Y-27632 protected ischemia/reperfusion induced injury of the liver through remarkable improvement of hepatic microcirculation, which was observed by intravital microscopy. Diamiter of sinusoid and postsinusoidal venule , sinusoidal perfusion rate were maintained as compared to sham group. Adherence of leucocytes in the sinusoid and postsinusoidal venule was much less, which results also in protection of disturbance of the blood flow. Y-27632 also exhibited to improve disturbance of microcirculation due to endotoxemia.