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Development of perioperative management for hepatic resection based on the stellate cell function

基于星状细胞功能的肝切除术围术期管理进展

基本信息

批准号：
14370355
负责人：
SHIMAHARA Yasuyuki
金额：
$ 8.9万
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：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370355/
关键词：
hepatic stellate cell thioredoxin ROCK Rho kinase inhibitor ischemia reperfusion injury hepatic microcirculation intravital microscopy N-acetylcisteine liver failure Rho kinase阻害剤肝繊維化急性肝不全肝腺維化

项目摘要

1)Relationship between thioredoxin and stellate cell function : Thioredoxin is a small redox-active protein with anti-oxidant and anti-apoptotic effect. We have investigated the protective effect of thioredoxin for hepatic fibrosis. Induction of endogenous thioredoxin was obvious in hepatocytes of thioacetamide-induced fibrotic liver of rats. Overexpression of thioredoxin inhibited tumor necrosis factor-(x-induced death of HepG2 cells. Thioacetamide-induced fibrosis and accumulation of malondialdehyde in the liver was suppressed in transgenic mice as compared with wild-type mice. Hepatic stellate cells isolated from transgenic mice was less proliferative than those isolated from wild type mice. Recombinant thioredoxin significantly inhibited DNA synthesis of primary-cultured stellate cells under serum or PDGF-BB stimulation. Thioredoxin failed to control collagen gene expression in cultured stellate cells. Thioredoxin has a potential to control hepatic fibrosis via inhibiting hepatocyt … More e death, proliferation of stellate cells and oxidative stress.2)Hepatic microcirculation and Rock/Rho kinase inhibitor, Y-27632 : Rock/Rho kinase inhibitor, Y-27632 is also known to prevent activation of hepatic stellate cell and prevent fibrosis. 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. Diameter 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.3)Effect of NAC (N-acetylcisteine) on clinical postoperative liver failure : NAC (N-acetylcisteine) was administered to a posthepatectomized patient with hyperbilirubinemia. Serum bilirubin level tended to decreased after enteral administration of NAC. Less

1）硫氧还蛋白与星状细胞功能的关系：硫氧还蛋白是一种小的氧化还原活性蛋白，具有抗氧化和抗凋亡作用。我们研究了硫氧还蛋白对肝纤维化的保护作用。硫代乙酰胺诱导的大鼠肝纤维化的肝细胞内源性硫氧还蛋白的诱导是明显的。硫氧还蛋白的过度表达抑制了肿瘤坏死因子-(x)诱导的HepG2细胞死亡。与野生型小鼠相比，转基因小鼠中硫代乙酰胺诱导的纤维化和丙二醛在肝脏中的积累受到抑制。从转基因小鼠中分离的肝星状细胞比从野生型小鼠中分离的肝星状细胞的增殖能力要低。硫氧还蛋白在血清或PDGF-BB刺激下显着抑制原代培养的星状细胞的DNA合成。硫氧还蛋白无法控制培养的星状细胞中的胶原蛋白基因表达。硫氧还蛋白具有通过抑制肝细胞死亡、星状细胞增殖和氧化应激来控制肝纤维化的潜力。2) 肝脏微循环和 Rock/Rho 激酶抑制剂，Y-27632 ： Rock/Rho 激酶抑制剂，Y-27632 还已知可防止肝星状细胞的活化并防止纤维化。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，血窦和窦后微静脉的直径、血窦灌注率保持不变。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。3)NAC（N-乙酰半胱氨酸）对临床术后肝衰竭的作用：将NAC（N-乙酰半胱氨酸）给予肝切除后患有高胆红素血症的患者。肠内给予NAC后血清胆红素水平呈下降趋势。较少的