Intestinal epithelial cells that line the mucosal surface of the gastrointestinal tract are positioned between an anaerobic lumen and a highly metabolic lamina propria. As a result of this unique anatomy, intestinal epithelial cells function within a steep physiologic oxygen gradient relative to other cell types. Furthermore, during active inflammatory disease such as IBD, metabolic shifts toward hypoxia are severe. Studies in vitro and in vivo have shown that the activation of hypoxia-inducible factor (HIF) serves as an alarm signal for the resolution of inflammation in various murine disease models. Amelioration of disease occurs, at least in part, through transcriptional up-regulation of non-classical epithelial barrier genes. There is much recent interest in harnessing hypoxia-inducible pathways, including targeting the hypoxia-inducible factor (HIF) and the proyl-hydroxylase enzyme (which stabilizes HIF), for therapy of IBD. Here, we review the signaling pathways involved and define how hypoxia may serve as an endogenous alarm signal for mucosal inflammatory disease. We also discuss the upside and potential downsides of targeting these pathways to treat patients with IBD.
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