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  

Effects of HIF-1αagonist or inhibitoron intestinal mucosal permeability in rats with sepsis

作　　者：王玉龙 滕文彬[1] 单跃 姚刘旭 何锐 李玉红[3] 祝胜美 WANG Yu-long;TENG Wen-bin;SHAN Yue;YAO Liu-xu;HE Rui;LI Yu-hong;ZHU Sheng-mei(Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000;Department of Anesthesiology, Shaoxing People's Hospital, Shaoxing 312000;Department of Anesthesiology,Shulan (Hangzhou) Hospital, Shulan International Medical College, Shuren University, Hangzhou 310004, China)

机构地区：[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

出　　处：《基础医学与临床》2021年第11期1618-1623,共6页Basic and Clinical Medicine

基　　金：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)。

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。Objective To investigate the effects of sepsis and HIF-1αagonist 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-1αagonist)/(sepsis+DMOG)group receiving intra-peritoneal injection of HIF-1αagonist DMOG(40 mg/kg)for 7 consecutive days before CLP,(sepsis+HIF-1αinhibitor)/(sepsis+BAY87-2243)group orally administered with HIF-1αinhibitor 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-1αand TJs protein expression were detected by Western blot.Results Sepsis caused pathological damage,increased permeability(P<0.05),up-regulation of HIF-1αand 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-1αagonist can significantly reduce intestinal mucosal permeability in sepsis,and this effect is significantly counteracted by its inhibitor.It is suggested that HIF-1αupregulation may protect intestinal mucosa aganist sepsis.

关 键 词：脓毒症 肠道黏膜通透性 低氧诱导因子1Α DMOG BAY87-2243 

分 类 号：R363[医药卫生—病理学]