Disturbed Oxygen Metabolism Induced by Perturbation of Microcirculation.

微循环扰动引起的氧代谢紊乱。

• 批准号: 01480226
• 负责人: SATO Nobuhiro
• 金额: $ 4.16万
• 依托单位: Juntendo University School of Medicine (1990)Osaka University (1989)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-01480226/
• 关键词: microcirculation; alcoholic liver disease; biomedical engineering; protooncogene; liver regeneration; tissue oxygenation; liver transplantation; hypoxia; 薬剤性肝障害; 肝移値; ヒポキシア; 肝微小循環; 肝血流; 肝酸素化; 白血球; 虚血性肝障害

There is an increasing body of evidence that the disturbance of microcirculation in hepatic lobules is involved in the pathogenesis of a wide variety of lever damage. Among them are alcohol-and drug-induced damage and liver injury caused by ischemia-reperfusion process, which occurs in case of major liver surgery including liver transplantation. To investigate the mechanisms of these liver damages and of liver regeneration process, we applied the medical-engineering technology and molecular biological techniques. For analyzing the hepatic microcirculation, we developed an in vivo super-magnified video microscopy system which allows us to monitor sinusoidal blood cell flow velocity and regional cellular oxygenation. Ethanol causes severe microcirculatory disturbances in midzone of hepatic lobule which could account for later tissue damage. CC1_4 and galactosamine also induced a microcirculatory change of the hepatic lobules which preceeded the liver damage. Microciroulatory disorder also plays an important role in liver transplantation. during regeneration of the liver following drug-induced liver damage. Expression of the protooncogenes and their products is specifically enhanced in parallel with increased DNA replication. Zonal heterogeneity of c-Ha-ras gane expression was evident, and a higher number of gene products was detected in the pericentral (PC) region than in periportal (PP) region after CC1_4-treatment, which caused a severe structural damage and microcirculatory disorder in PC region. Protein kinase C, an important protein in signal transduction, also shows heterogeneous activation (more in PC than in PP) during liver regeneration, which might trigger cellular functions and proliferation and mediate the biological action of hepatotrophic factors. In conclusion, the microcirculatory disorder has a role in pathogenesis and repair process of alcohol-and drug-induced liver damage and following liver transplantation.

越来越多的证据表明，肝小叶微循环障碍参与了多种肝杠杆损伤的发病机制。其中包括酒精和药物性损伤以及肝缺血再灌注过程引起的肝损伤，主要发生在肝移植等重大肝脏手术中。应用医学工程技术和分子生物学技术，探讨肝损伤的发生机制和肝再生过程。为了分析肝脏微循环，我们开发了一种体内超放大视频显微镜系统，使我们能够监测正弦血流速度和区域细胞氧合。乙醇引起肝小叶中间区严重的微循环紊乱，这可能导致后期的组织损伤。CC1_4和半乳糖胺也在肝损伤前引起肝小叶微循环改变。微循环障碍在肝移植中也起着重要作用。药物性肝损伤后肝脏再生过程中。原癌基因及其产物的表达随着DNA复制的增加而特异性增强。c-Ha-ras基因表达具有明显的区域异质性，cc1_4处理后，在中央周围（PC）区检测到的基因产物数量高于门静脉周围（PP）区，导致PC区严重的结构损伤和微循环障碍。蛋白激酶C是信号转导的重要蛋白，在肝脏再生过程中也表现出异质活化（PC比PP更多），可能触发细胞功能和增殖，介导肝营养因子的生物学作用。综上所述，微循环障碍在酒精和药物性肝损伤及肝移植后的发病机制和修复过程中具有一定的作用。

项目成果

Lieber CS: "Impaired oxygen utilization.A new mechanism for the hepatotoxicity of ethanol in subーhuman primates." J Clin Invest. 83. 1682-1690 (1989)

Lieber CS：“氧气利用受损。乙醇对亚人类灵长类动物的肝毒性的新机制。”J Clin Invest。83。1682-1690（1989）

Tsujii S, Sato N, Kawano S, Hayashi N, Tsujii M, et al.: "Evaluation of oxygen metabolism in digestive organs using computer-assisted electronic endoscopy." Gastroenterology. 96. 517 (1989)

Tsujii S、Sato N、Kawano S、Hayashi N、Tsujii M 等人：“使用计算机辅助电子内窥镜评估消化器官中的氧代谢。”

Hijioka T, Sato N, Matsumura T, Yoshihara H, Fukui H, et al.: "Role of vasoconstriction in disturbed microcirculation of the liver after etanol load." Gastroenterology. 96. 608 (1989)

Hijioka T、Sato N、Matsumura T、Yoshihara H、Fukui H 等人：“血管收缩在乙醇负荷后肝脏微循环紊乱中的作用。”

Yuki T, Yoshitoku K, Nakagawa Y, Okanoue T, Fukui H, et al.: "Effect of coenzyme Q10 (CoQ10) on the hepatic lipid peroxidation and mitochondrial damage n alcohol-treated rats." Gastroenterology. 96. 675 (1989)

Yuki T、Yoshitoku K、Nakakawa Y、Okanoue T、Fukui H 等人：“辅酶 Q10 (CoQ10) 对酒精治疗大鼠肝脂质过氧化和线粒体损伤的影响。”

Katayama K, Hayashi N, Sasaki Y, Kasahara A, et al.: "Detection of hepatitis B virus X gene protein and antibody in type B chronic liver disease." Gastoenterology. 97. 990-998 (1989)

Katayama K，Hayashi N，Sasaki Y，Kasahara A，等：“乙型肝炎病毒X基因蛋白和抗体在乙型慢性肝病中的检测”。