缺氧诱导因子-2α在小鼠DSS结肠炎中的作用及其机制研究  

Effect of Hypoxia-inducible Factor-2α on Mice DSS Colitis and its Possible Mechanism

作　　者：张顺[1] 杜涛[1] 蒋小华[1] 宋纯[1] 

机构地区：[1]上海市东方医院(同济大学附属东方医院)胃肠外科,200127

出　　处：《胃肠病学》2017年第2期91-95,共5页Chinese Journal of Gastroenterology

摘　　要：背景:对炎症性肠病(IBD)发病机制的研究发现微循环缺氧是IBD的重要特征之一,转录因子缺氧诱导因子(HIFs)在缺血缺氧损伤的调节中起关键作用。目的:探讨HIF-2α在小鼠葡聚糖硫酸钠(DSS)结肠炎中的作用及其可能机制。方法:以Mx-Cre/LoxP重组方法获得HIF-2α基因条件性敲除(HIF-2α-/-)小鼠,将C57BL/6、HIF-2α+/+和HIF-2α-/-小鼠分别随机分入DSS模型组和饮水对照组,前者予4%DSS溶液自由饮用7 d制作结肠炎模型,造模过程中每天评估疾病活动指数(DAI)。各组小鼠分别于造模开始后第1、3、5、7 d处死,取结肠组织观察组织病理学变化,real-time PCR检测HIF-2α、肿瘤坏死因子-α(TNF-α)mRNA表达。结果:造模过程中,C57BL/6和HIF-2α+/+DSS模型组小鼠结肠黏膜HIF-2αmRNA表达明显升高,DAI和结肠黏膜炎症评分显著高于C57BL/6饮水对照组(第5、第7 d,P<0.05)。HIF-2α-/-DSS模型组小鼠结肠黏膜炎症损伤较HIF-2α+/+DSS模型组进一步加重,DAI和炎症评分进一步升高(除第7 d炎症评分外,P均<0.05),结肠黏膜TNF-αmRNA表达亦较HIF-2α+/+DSS模型组显著升高(第5、第7 d,P<0.05)。结论:HIF-2α可能通过抑制TNF-α表达发挥减轻小鼠DSS结肠炎炎症损伤的作用。Background： There is increasing evidence that microcirculation hypoxia plays an important role in pathogenesis of inflammatory bowel disease （IBD）. Hypoxia-inducible factors （HIFs） are transcriptional factors that serve as master regulators in ischemic and hypoxia injuries. Aims： To investigate the effect of HIF-2ct on dextran sulfate sodium （DSS）- induced colitis in mice and its possible mechanism. Methods： Mx-Cre/LoxP recombination system was utilized to establish a conditional HIF-2α gene knockout （HIF-2α -/- ） mouse model. C57BL/6, HIF-2α ＋/＋ and HIF-2α -/- mice were randomly allocated into DSS colitis group and water drinking group, respectively. Experimental colitis was induced by treatment with 4% DSS in drinking water for 7 days, and the disease activity index （DAI） was assessed daily. Mice in each group were sacrificed on day 1, 3, 5 and 7 in batch; the histopathological changes of colonic tissue were observed, and mRNA expressions of HIF-2α and tumor necrosis factor-or （TNF-ot） were measured by real-time PCR. Results： During model establishment, expression of HIF-2α mRNA in colonic tissue was elevated in C57BL/6 and HIF-2ct ＋/＋ DSS colitis groups, and the DAI and colonic inflammatory score were significantly higher than those in C57BL/6 water drinking group （P 〈0.05 on day 5 and day 7）. Compared with HIF-2α ＋/＋ DSS colitis group, HIF-2ct -/- DSS colitis group had more severe colonic inflammatory injury and the DAI and inflammatory score were further increased （P all 〈 0.05, except the inflammatory score on day 7 ） ; expression of TNF-ot mRNA in colonic tissue was also increased significantly in HIF-2α - / - DSS colitis group （ P 〈 0.05 on day 5 and day 7 ）. Conclusions： HIF-2α may ameliorate colonic inflammatory injury in mice with DSS colitis via inhibition of TNF-α expression.

关 键 词：结肠炎 缺氧诱导因子2 Α亚基 肿瘤坏死因子Α 小鼠 基因敲除 

分 类 号：R574.62[医药卫生—消化系统]