Journal
NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY
Volume 14, Issue 10, Pages 596-611Publisher
NATURE PORTFOLIO
DOI: 10.1038/nrgastro.2017.101
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Funding
- Research Foundation of Flanders (FWO) [G075312]
- Special Research Fund (BOF) of Ghent University, Belgium [GOA 2012/01G00812, GOA 2017000902]
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Tissue hypoxia occurs when local oxygen demand exceeds oxygen supply. In chronic inflammatory conditions such as IBD, the increased oxygen demand by resident and gut-infiltrating immune cells coupled with vascular dysfunction brings about a marked reduction in mucosal oxygen concentrations. To counter the hypoxic challenge and ensure their survival, mucosal cells induce adaptive responses, including the activation of hypoxia-inducible factors (HIFs) and modulation of nuclear factor-kappa B (NF-kappa B). Both pathways are tightly regulated by oxygen-sensitive prolyl hydroxylases (PHDs), which therefore represent promising therapeutic targets for IBD. In this Review, we discuss the involvement of mucosal hypoxia and hypoxia-induced signalling in the pathogenesis of IBD and elaborate in detail on the role of HIFs, NF-kappa B and PHDs in different cell types during intestinal inflammation. We also provide an update on the development of PHD inhibitors and discuss their therapeutic potential in IBD.
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