Effect of Hypoxia-inducible Factor-2αon Mice DSS Colitis and its Possible Mechanism / 胃肠病学

ABSTRACT

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-2αon 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-2αgene 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-2αand tumor necrosis factor-α(TNF-α)were measured by real-time PCR.Results:During model establishment,expression of HIF-2αmRNA in colonic tissue was elevated in C57BL/6 and HIF-2α+/+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-2α-/-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-αmRNA in colonic tissue was also increased significantly in HIF-2α-/-DSS colitis group (P<0.05 on day 5 and day 7).Conclusions:HIF-2αmay ameliorate colonic inflammatory injury in mice with DSS colitis via inhibition of TNF-αexpression.