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。

• 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

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.

本研究旨在探讨肝窦细胞，尤其是枯否细胞在各种实验性肝损伤中的作用。本研究探讨了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，并研究了与大鼠Kupffer细胞共培养的肝癌细胞的代谢变化。来自枯否细胞的NO诱导肿瘤细胞的线粒体功能障碍，随后是肝窦膜屏障功能障碍。与肝癌细胞共培养的库普弗细胞中iNOS及iNOSmRNA表达增加。CD 18/ICAM-1依赖的细胞与肝癌细胞的相互作用引起钙动员和NF-κ B的氧化激活，这可能导致Kupffer细胞中NO的产生增加。酒精性肝损伤模型显示，酒精可使枯否细胞释放超氧阴离子进入肝窦，导致肝窦内皮细胞损伤。枯否细胞通过细胞色素P450 2 E1代谢乙醇。慢性乙醇灌胃后，小剂量LPS可引起微循环障碍。显示白细胞表面粘附分子的表达和白细胞在血窦内的粘附。

项目成果

Ohki E, Kato S, et al.: "Chronic ethanol consumption enhances endotoxin induced hepatic sinusoidal leukocyte adhesion." Alcoholism : Clin Exp Res. 20. 350A-355A (1996)

Ohki E、Kato S 等人：“长期饮酒会增强内毒素诱导的肝窦白细胞粘附。”

Hirokazu Yokoyama et al: "Formation of Superoxide Anion in the Hepatic Sinusoid after Lipopolysaccharide Challenge" Alcoholism,Clin Exp Res. Vol.22・3. 133S-136S (1998)

Hirokazu Yokoyama 等：“脂多糖挑战后肝窦中超氧阴离子的形成”酒精中毒，临床实验研究第 22 卷 133S-136S（1998 年）。

Higuchi H,Kurose I,Kato S,Miura S,Ishii H: "Ethanol-induced oxidative stress and apoptosis. Alcoholism" Clin Exp Res. 20 (9). 340A-346A (1996)

Higuchi H，Kurose I，Kato S，Miura S，Ishii H：“乙醇诱导的氧化应激和细胞凋亡。酒精中毒”临床实验研究。

Horie Y,Kato S,Ohki E,et al: "Effect of lipopolysaccharides on erythrocyte flow velocity in rat liver." J.Gastroenterol. 32. 783-790 (1997)

Horie Y，Kato S，Ohki E，et al：“脂多糖对大鼠肝脏红细胞流速的影响”。

Yokoyama H,Fukuda M,Okamura S,et al: "Formation of superoxide anion in the hepatic sinusoid after lipopolysaccharide challenge" Alcoholism : Clin Exp Res. 22. 133A-136A (1998)

Yokoyama H、Fukuda M、Okamura S 等人：“脂多糖挑战后肝窦中超氧阴离子的形成”酒精中毒：临床实验研究。