基础医学与临床 ›› 2021, Vol. 41 ›› Issue (11): 1618-1623.

• 研究论文 • 上一篇    下一篇

HIF-1α激动剂或拮抗剂对脓毒症大鼠肠道黏膜通透性的影响

王玉龙1,2, 滕文彬1, 单跃2, 姚刘旭2, 何锐2, 李玉红3*, 祝胜美1*   

  1. 1.浙江大学医学院附属第一医院 麻醉科, 浙江 杭州 310000;
    2.绍兴市人民医院 麻醉科,浙江 绍兴 312000;
    3.树人大学树兰国际医学院附属树兰(杭州)医院 麻醉科, 浙江 杭州 310004
  • 收稿日期:2020-10-09 修回日期:2020-12-31 发布日期:2021-10-27
  • 通讯作者: *Yuh_li@zju.edu.cn; smzhu20088@zju.edu.cn
  • 基金资助:
    浙江省科学技术厅公益项目(LY21H150001、LGF19H030011);浙江省医药卫生科技计划项目(2020KY329,2019306157)

Effects of HIF-1α agonist or inhibitor on intestinal mucosal permeability in rats with sepsis

WANG Yu-long1,2, TENG Wen-bin1, SHAN Yue2, YAO Liu-xu2, HE Rui2, LI Yu-hong3*, ZHU Sheng-mei1*   

  1. 1. Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000;
    2. Department of Anesthesiology, Shaoxing People's Hospital, Shaoxing 312000;
    3. Department of Anesthesiology, Shulan (Hangzhou) Hospital, Shulan International Medical College, Shuren University, Hangzhou 310004, China
  • Received:2020-10-09 Revised:2020-12-31 Published:2021-10-27
  • Contact: *Yuh_li@zju.edu.cn; smzhu20088@zju.edu.cn

摘要: 目的 探讨脓毒症(sepsis)和HIF-1α激动或拮抗剂对肠道黏膜屏障(IMB)功能的影响。方法 将SD大鼠随机分假手术组(sham)、sepsis组[sepsis,用盲肠结扎穿孔(CLP)建立sepsis模型]、(sepsis+HIF-1α激动剂)/(sepsis + DMOG)组[CLP术前连续7 d腹腔注射HIF-1α激动剂DMOG(40 mg/kg)]、(sepsis+HIF-1α拮抗剂)/(sepsis + BAY 87-2243)组,[CLP术前连续3 d口服灌胃HIF-1α抑制剂BAY87-2243(9 mg/kg)],各6只。ELISA检测大鼠血浆肠黏膜通透性标志物二胺氧化酶(DAO)、肠型脂肪酸结合蛋白2(FABP2)、D-乳酸和荧光素标记的右旋糖苷(FD4);HE染色检测大鼠肠黏膜形态学改变;Western blot检测大鼠肠黏膜缺氧诱导因子-1(HIF-1α)以及紧密连接(TJs)蛋白表达。结果 Sepsis致大鼠肠黏膜病理形态学破坏、通透性增加(P<0.05)、HFI-1α表达上调、TJs表达下调(P<0.05);加入DMOG能减轻肠黏膜病理损伤、降低肠黏膜通透性(P<0.05);而大鼠经过BAY87-2243处理得出相反的结果。结论 HIF-1α激动剂能明显降低sepsis大鼠肠道黏膜通透性,其抑制剂作用相反。表明脓毒性肠黏膜损伤,HIF-1α上调可能对肠黏膜具有保护作用。

关键词: 脓毒症, 肠道黏膜通透性, 低氧诱导因子1α, DMOG, BAY87-2243

Abstract: Objective To investigate the effects of sepsis and HIF-1α agonist or inhibitor on intestinal mucosal barrier(IBM) function. Methods SD rats were randomly divided into four groups with 6 in each as follows:sham operation group (sham), sepsis group treated with cecal ligation and perforation (CLP), (sepsis+HIF-1α agonist)/(sepsis+DMOG) group receiving intra-peritoneal injection of HIF-1α agonist DMOG (40 mg/kg) for 7 consecutive days before CLP, (sepsis+HIF-1α inhibitor)/(sepsis+BAY87-2243) group orally administered with HIF-1α inhibitor BAY87-2243(9 mg/kg) for 3 consecutive days before CLP. Plasma intestinal permeability markers of diamine oxidase (DAO), intestinal type fatty acid binding protein 2 (FABP2), D-lactic acid and fluorescein isothiocyanate-dextran (FD4) were detected by ELISA. Morphological changes of intestinal mucosa were detected by HE staining. HIF-1α and TJs protein expression were detected by Western blot. Results Sepsis caused pathological damage, increased permeability (P<0.05), up-regulation of HIF-1α and down-regulation of tight junctions (TJs) expression in intestinal mucosa of rats with sepsis(P<0.05); Addition of DMOG alleviated intestinal mucosal pathological damage and decreased intestinal mucosal per- meability (P<0.05); While rats treated with BAY87-2243 showed the opposite result. Conclusions HIF-1α agonist can significantly reduce intestinal mucosal permeability in sepsis, and this effect is significantly counteracted by its inhibitor. It is suggested that HIF-1α upregulation may protect intestinal mucosa aganist sepsis.

Key words: sepsis, intestinal mucosal permeability, hypoxia inducible factor 1α, DMOG, BAY87-2243

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