Hypoxia: an alarm signal during intestinal inflammation.
Hypoxia: an alarm signal during intestinal inflammation.
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DOI：
10.1038/nrgastro.2010.39
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发表时间：
2010-05
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--
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--
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排列在胃肠道粘膜表面的肠上皮细胞位于厌氧腔和高度代谢的固有层之间。由于这种独特的解剖结构，肠上皮细胞相对于其他细胞类型在陡峭的生理氧梯度内发挥作用。此外，在活动性炎症性疾病如IBD期间，代谢向缺氧的转变是严重的。体外和体内研究表明，缺氧诱导因子（HIF）的激活在各种小鼠疾病模型中充当炎症消退的警报信号。疾病的改善至少部分地通过非经典上皮屏障基因的转录上调而发生。最近，人们对利用低氧诱导途径（包括靶向低氧诱导因子（HIF）和脯氨酰羟化酶（稳定HIF））治疗IBD非常感兴趣。在这里，我们回顾了相关的信号通路，并定义了缺氧如何作为粘膜炎性疾病的内源性警报信号。我们还讨论了靶向这些途径治疗IBD患者的优点和潜在缺点。
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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