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Regulation of hepatic micro circulation by hepatic stellate cell-Application of NAC to liver failure

肝星状细胞对肝脏微循环的调节——NAC在肝衰竭中的应用

基本信息

批准号：
13557100
负责人：
SHIMAHARA Yasuyuki
金额：
$ 8.64万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557100/
关键词：
hepatic stellate cell hepatic microcirculation Liver failure Intravital microscopyu Liver fibrosis ROCK Rho kinase inhibitor Y-27632 enndotoxin 肝障害虚血再潅流障害

项目摘要

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 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 hemi-lateral 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. Tioredoxin has an effect of antioxidant like NAC. We clarified that thioredoxin prevents hepatic fibrosis in the chronic liver injury model and also protect hepatic cell death in acute hepatitis model.

肝星状细胞。已知通过其收缩和舒张来调节肝窦血流。当它因激活而收缩时，正弦血流量就会减少。因此，认为调节肝星状细胞的活化可能是改善肝脏微循环的潜在策略。我们在 TAA 诱导的大鼠肝硬化模型中阐明，N-乙酰基-L-半胱氨酸 (NAC) 对预防肝星状细胞活化和纤维化进展具有强大作用。在这样的模型中，微循环得到了很好的维持。 Rock/Rho 激酶抑制剂 Y-27632 还可以防止肝星状细胞活化并防止纤维化。在本研究中，我们检查了Y-27632是否具有改善肝脏微循环的作用。我们使用肝脏半侧钳在大鼠肝脏缺血/再灌注模型中对其进行了研究。通过活体显微镜观察到，Y-27632 通过显着改善肝脏微循环来保护缺血/再灌注引起的肝脏损伤。与假手术组相比，血窦和血窦后微静脉的直径、血窦：灌注率得以维持。血窦和窦后微静脉中白细胞的粘附要少得多，这也导致血流紊乱的保护。 Y-27632 还表现出改善内毒素血症引起的微循环障碍的作用。硫氧还蛋白与NAC一样具有抗氧化作用。我们阐明硫氧还蛋白可以预防慢性肝损伤模型中的肝纤维化，并且还可以保护急性肝炎模型中的肝细胞死亡。