Role of oxidative stress and microcirculatory disturbances in the liver injury.

氧化应激和微循环障碍在肝损伤中的作用。

• 批准号: 05454248
• 负责人: ISHII Hiromasa
• 金额: $ 4.35万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454248/
• 关键词: microcirculatory disturbance; oxidative stress; liver injury; prostagrandin; endotoxin; nitric oxide; alcohol; ブロスタグランディン

Pathogenetical role of oxidative stress and microcirculatory disturbances were investigated by experimental model in vivo and in perfused rat liver. To that effect, intravital fluorescence microscopy assisted by ultrasensitive camera and various fluorescence probes were used. Ischemica reperfusion injury was demonstrated to star from midzone of the hepatic lobule and extended to pericentral area. This was inhibited by xanthine oxidase inhibitor and prostagrandin E1. Microcirculatory disturbances in acute ethanol intoxication was demonstrated with fluorescence labeled RBC,at high ethanol concentration but not at low ethanol concentration. Increase of hepatic NADH in centrilobular area was also demonstrated in vivo as well as perfused liver. Endotoxin induced liver injury was demonstrated to be mediated by mitochondrial dysfunction by the release of nitric oxide from Kupffer cell. This was blocked by NO inhibitor such as L-NMMA and i-NOS inhibitor. In these experimental hepatic injury, oxidative stress and microcirculatory disturbances playd an important role in pathogenesis.

通过在体实验模型和大鼠肝脏灌流实验，研究了氧化应激和微循环障碍在肝损伤中的作用。为此，活体荧光显微镜辅助超灵敏相机和各种荧光探针。缺血再灌注损伤以肝小叶中部为星星，并向中央周围区扩展。黄嘌呤氧化酶抑制剂和野牡丹素E1可抑制此作用。用荧光标记红细胞显示急性乙醇中毒时的微循环障碍，在高浓度乙醇时，而在低浓度乙醇时则无。在体内和灌注的肝脏中也证明了小叶中心区的肝脏NADH增加。内毒素诱导的肝损伤是由枯否细胞释放一氧化氮引起的线粒体功能障碍介导的。NO抑制剂如L-NMMA和i-NOS抑制剂可阻断此作用。在这些实验性肝损伤中，氧化应激和微循环障碍在发病机制中发挥重要作用。

项目成果

Kurose I.: "Nitric oxide mediates lipopoly saccharide-induced alteration of mitochondrial function in cultured hepatocytes" Hepatology. 18(2). 380-388 (1993)

Kurose I.：“一氧化氮介导脂多糖诱导的培养肝细胞线粒体功能的改变”肝病学。

Suzuki H.et al: "Prostagrandin E1 attenuates early stress preceeding zone specific oxidative injury in hypoperfused rat liver." J Clin Invest. 93. 155-164 (1994)

Suzuki H.et al：“前列腺素 E1 可以减轻低灌注大鼠肝脏早期应激前区特异性氧化损伤。”

Suzuki H.: "Prustagrandin(PG)E,atlenuates early stress Preceeding zune Specific oxidative injury in hyproperfused rat liver" J.Clin.Invest. 93(1). 155-164 (1994)

Suzuki H.：“Prustagrandin(PG)E，减轻过度灌注大鼠肝脏中先前 zune 的早期应激特异性氧化损伤”J.Clin.Invest。

Suzuki H.: "Prostagrandin (PG)E,attenuates early stress preceedings zone specific oxidative injury inhypoperfused rat liver" J Clin Invest. 93(1). 155-164 (1994)

Suzuki H.：“前列腺素 (PG)E 可减轻低灌注大鼠肝脏中早期应激区域特异性氧化损伤”J Clin Invest。

末松 誠: "肝微小循環障害時の活性酸素依存性細胞障害に対するPGE_1の効果" 現代医療. 24(増). 3495-3502 (1992)

Makoto Suematsu：“PGE_1 对肝微循环障碍期间活性氧依赖性细胞损伤的影响”现代医学 24（in）。