Molecularbiological study for the role of sinusoidal cells in pathogenesis of liver disease.

肝窦细胞在肝病发病机制中作用的分子生物学研究。

基本信息

批准号：
08407016
负责人：
ISHII Hiromasa
金额：
$ 17.41万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08407016/
关键词：
Kupffer cells Sinusoidal cells Mitochondrion NO TNF-alpha NF-kB Endotoxin Alcohol TNFα NF-kB 肝疾患接着因子カルシウム NF-κB アポトーシス

项目摘要

Aim of this study is to investigate the role of sinusoidal cells, especially Kupffer cells, on various experimental liver injuries. Oxidative stress and release of nitric oxide by Kupffer cells analyzed in relation to hepatocyte injury and apoptosis.The metabolic changes in hepatoma cells co-cultured with isolated rat Kupffer cells were investigated. NO from Kupffer cells induced mitochondrial dysfunction in tumor cells followed by membrane barrier dysfunction in the liver sinusoid. Increased expression of iNOS and iNOS mRNA in the Kupffer cells co-cultured with hepatoma cells was shown. It is also suggested that CD 18/ICAM-1 dependent cell-to-cell interaction with hepatoma cells causes calcium mobilization and oxidative activation of NF-kB , which may lead to the increase production of NO in Kupffer cells. Kupffer cells stimulated by lipopolysaccharides was also shown to release NO and TNF-a, which resulted in mitochondrial injury in hepatocyte.Experimental model of alcoholic liver damage in perfused liver showed that superoxide anion was released from Kupffer cells into sinusoid by ethanol administration, and lead to damage in sinusoidal endothelial cells. Kupffer cells were shown to metabolize ethanol by cytochrome P450 2E1. After chronic ethanol feeding, LPS elicited microcirculatory disturbance with smaller dose. Expression of adhesion molecules on leukocytes, and adhesion of leukocytes in sinusoid was shown.

本研究的目的是探讨肝窦细胞，特别是库普弗细胞，在各种实验性肝损伤中的作用。分析Kupffer细胞的氧化应激和一氧化氮释放与肝细胞损伤和凋亡的关系。研究了与分离的大鼠Kupffer细胞共培养的肝癌细胞的代谢变化。来自库普弗细胞的 NO 诱导肿瘤细胞线粒体功能障碍，随后导致肝窦膜屏障功能障碍。与肝癌细胞共培养的 Kupffer 细胞中 iNOS 和 iNOS mRNA 的表达增加。还表明 CD 18/ICAM-1 依赖性细胞间相互作用与肝癌细胞引起钙动员和 NF-kB 氧化激活，这可能导致 Kupffer 细胞中 NO 的产生增加。脂多糖刺激的库普弗细胞也被证明可以释放NO和TNF-a，从而导致肝细胞线粒体损伤。灌注肝脏酒精性肝损伤的实验模型表明，通过乙醇注射，库普弗细胞将超氧阴离子释放到肝窦中，并导致肝细胞内的线粒体损伤。导致窦内皮细胞损伤。 Kupffer 细胞通过细胞色素 P450 2E1 代谢乙醇。长期喂食乙醇后，较小剂量的LPS即可引起微循环障碍。显示白细胞上粘附分子的表达以及血窦中白细胞的粘附。