Department of Gastroenterology, Ghent University, De Pintelaan 185, 1K12-E, 9000 Ghent, Belgium.
Robarts Clinical Trials West, 4350 Executive Drive 210, San Diego, California 92121, USA.
Nat Rev Gastroenterol Hepatol. 2017 Oct;14(10):596-611. doi: 10.1038/nrgastro.2017.101. Epub 2017 Aug 30.
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-κB (NF-κB). 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-κB 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.
当局部氧气需求超过氧气供应时，就会发生组织缺氧。在慢性炎症性疾病如 IBD 中，常驻和肠道浸润免疫细胞的增加的氧气需求加上血管功能障碍导致黏膜氧浓度显著降低。为了应对缺氧挑战并确保其存活，黏膜细胞诱导适应性反应，包括缺氧诱导因子 (HIFs)的激活和核因子-κB (NF-κB)的调节。这两条途径都受到氧敏感脯氨酰羟化酶 (PHD)的严格调节，因此它们是治疗 IBD 的有前途的治疗靶点。在这篇综述中，我们讨论了黏膜缺氧和缺氧诱导信号在 IBD 发病机制中的作用，并详细阐述了 HIFs、NF-κB 和 PHDs 在肠道炎症中不同细胞类型中的作用。我们还提供了 PHD 抑制剂的最新进展，并讨论了它们在 IBD 中的治疗潜力。
