Mechanism of gut ischemia/reperfusion-induced intestinal and hepatic injury

肠道缺血/再灌注引起肠肝损伤的机制

• 批准号: 11670532
• 负责人: HORIE Yoshinori
• 金额: $ 2.3万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670532/
• 关键词: ischemia; reperfusion; microcirculation; ethanol; cytokines; vasoactive agents; endotoxin; nitric oxide; intestinal mucosal permeability

Male Wistar rats were exposed to gut ischemia for 30 min followed by reperfusion. Intravital videomicroscopy was used to monitor leukocyte recruitment and the number of nonperfused sinusoids (NPS). Plasma ALT, tumor necrosis factor (TNF)-α and endotoxin levels as well as intestinal mucosal permeability (IMP) were also monitored. In separate experiments, ethanol was administered (by gastric tube) before gut ischemia. Same experiments wee peformed in male Wistar rats, pair-fed for 6 weeks with either a liquid diet containing EtOH or an isocaloric control diet. In control rats, gut I/R increased the number of stationary leukocytes and NPS.It also elevated the plasma ALT, TNF-α and endotoxin levels, with a corresponding increase in IMP.Low-dose ethanol consumption blunted gut I/R-induced leukostasis in the midzonal region and it reduced the I/R-induced elevations in plasma TNF-α and ALT.However, high-dose ethanol consumption aggravated the gut I/R-induced increases in leukostasis in the pe … More ricentral region and it exacerbated the increases in plasma endotoxin and ALT.Ethanol consumption, at either dose, did not affect the gut I/R-induced increase in the IMP.Pretreatment with an NO synthase inhibitor, NG-monomethyl-L-arginine, diminished the protective effects of low dose ethanol. In rats fed EtOH chronically, the gut I/R-induced increases in NPS and leukostasis were blunted in the midzonal region, while exaggerated letukostasis was noted in the pericentral region and terminal hepatic venules (THV). Chronic EtOH consumption also enhanced the gut I/R-induced increase in plasma ALT levels. The exaggerated responses to gut I/R normally seen in EtOH-fed rats, were largely prevented by pretreatment with a blocking anti ICAM-1 monoclonal antibody. These results suggest that low-dose ethanol consumption attenuates the hepatic imflammatory responses, microvascular dysfunction and hepatocellular injury elicited by gut I/R via an increase in sinusoidal NO levels, while high-dose ethanol consumption appears to significantly aggravate these gut I/R-induced responses. These results also suggest that chronic EtOH consumption enhances the gut I/R-induced hepatic microvascular dysfunction in the pericentral region and THV by an enhanced expression of ICAM-1, which may contribute to the corresponding enhancement of liver (hepatocellular) injury. Less

雄性Wistar大鼠暴露于肠缺血30分钟，然后再灌注。活体视频显微镜用于监测白细胞募集和非灌注血窦（NPI）的数量。同时监测血浆ALT、肿瘤坏死因子（TNF）-α和内毒素水平以及肠粘膜通透性（IMP）。在单独的实验中，在肠缺血前给予乙醇（通过胃管）。同样的实验在雄性Wistar大鼠中进行，用含有EtOH的液体饮食或等热量对照饮食配对喂养6周。在对照组大鼠中，肠I/R可增加静止白细胞和白细胞计数，同时升高血浆ALT、TNF-α和内毒素水平，并相应增加IMP。低剂量乙醇消耗可减弱肠I/R诱导的中带区白细胞停滞，并降低I/R诱导的血浆TNF-α和ALT升高。然而，高剂量乙醇消耗可加重肠I/R诱导的白细胞停滞。 ...更多信息 在任何剂量下，乙醇的消耗都不影响肠I/R诱导的IMP增加。用NO合酶抑制剂NG-单甲基-L-精氨酸预处理，降低了低剂量乙醇的保护作用。在长期喂食EtOH的大鼠中，肠I/R诱导的胆汁和白细胞停滞增加在中间区减弱，而在中央周围区和终末肝小静脉（THV）中观察到过度的letukostasis。慢性乙醇消耗也增强了肠道I/R诱导的血浆ALT水平升高。在EtOH喂养的大鼠中通常观察到的对肠道I/R的过度反应在很大程度上通过用阻断性抗ICAM-1单克隆抗体预处理来防止。这些结果表明，低剂量乙醇消耗减弱肝脏炎症反应，微血管功能障碍和肝细胞损伤引起的肠道I/R通过增加正弦NO水平，而高剂量乙醇消耗似乎显着加剧这些肠道I/R诱导的反应。这些结果还表明，慢性EtOH消耗增强肠道I/R诱导的肝微血管功能障碍的中央周围区和THV的ICAM-1的表达增强，这可能有助于相应的增强肝脏（肝细胞）损伤。少

项目成果

Yamagishi Y, Horie Y, et al.: "Effects of high dose ethanol on gut ischemia/reperfusion-induced microvascular dysfunction in theliver."Alcohol and Biochemical Research. Vol 19. 37-41 (1999)

Yamagishi Y、Horie Y 等人：“高剂量乙醇对肠道缺血/再灌注引起的肝脏微血管功能障碍的影响。”酒精和生化研究。

堀江義則,山岸由幸 他: "アルコール関連障害のリスク因子に関する最近のトピックスー肝微小循環障害からの検討"アルコールと医学生物学. 20. 20-28 (2000)

Yoshinori Horie、Yoshiyuki Yamagishi 等人：“从肝脏微循环障碍的角度探讨酒精相关疾病的危险因素的最新主题”《酒精与医学生物学》，2000 年 20 月 20 日。

山岸由幸,堀江義則 他: "腸管虚血再灌流惹起性肝障害に対する高用量エタノールの影響"アルコールと医学生物学. 19. 37-41 (1999)

Yoshiyuki Yamagishi、Yoshinori Horie 等人：“高剂量乙醇对肠缺血再灌注引起的肝损伤的影响”《酒精与医学生物学》19. 37-41 (1999)。

Ishii H, Yokoyama H, Horie Y.: "Recent topics of alcoholic liver disease : basic and clinical aspects."Nippon Shokakibyo Gakkai Zasshi. 97. 877-887 (2000)

Ishii H、Yokoyama H、Horie Y.：“酒精性肝病的最新主题：基础和临床方面。”Nippon Shokakibyo Gakkai Zasshi。

堀江義則,山岸由幸 他: "アルコール関連障害のリスク因子に関する最近のトピックスー肝微小管循環障害からの検討"アルコールと医学生物学. 20. 20-28 (2000)

Yoshinori Horie、Yoshiyuki Yamagishi 等人：“从肝微管循环障碍的角度探讨酒精相关疾病的危险因素的最新主题”《酒精与医学生物学》20. 20-28 (2000)。