The role of hypoxia in intestinal inflammation.
The role of hypoxia in intestinal inflammation.
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DOI：
10.1186/s40348-016-0030-1
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Shah YM
中科院分区：
文献类型：
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作者：
Shah YM
炎症性肠病（IBD）是一种慢性复发性肠道炎症性疾病。IBD是一种多因素疾病，IBD相关基因在先天免疫反应、炎症反应、自噬和上皮屏障完整性中至关重要。此外，上皮氧张力在IBD的肠道炎症和消退中起关键作用。肠具有细胞氧张力的动态和快速波动，其在IBD中失调。肠上皮细胞具有陡峭的氧梯度，其中绒毛的尖端缺氧，并且绒毛的基部处的氧合增加。IBD导致整个粘膜缺氧加剧。缺氧信号通过一个高度保守的转录因子家族传递，其中缺氧诱导因子（HIF）-1α和HIF-2α在维持肠道内稳态中至关重要。在炎症粘膜中，HIF-1α增加屏障保护基因，增强保护性先天免疫应答，并通过增加β-防御素激活抗菌应答。HIF-2α在维持急性损伤后上皮诱导的炎症反应以及肠的再生和增殖能力方面是必不可少的。结肠炎中的HIF-1α激活导致保护性反应，而HIF-2α的慢性激活增加促炎反应、肠损伤和癌症。在这篇简短的综述中，我们详细介绍了HIF-1α和HIF-2α在肠道炎症和损伤中的作用以及靶向HIF信号转导在IBD中的治疗意义。
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestine. IBD is a multifactorial disorder, and IBD-associated genes are critical in innate immune response, inflammatory response, autophagy, and epithelial barrier integrity. Moreover, epithelial oxygen tension plays a critical role in intestinal inflammation and resolution in IBD. The intestines have a dynamic and rapid fluctuation in cellular oxygen tension, which is dysregulated in IBD. Intestinal epithelial cells have a steep oxygen gradient where the tips of the villi are hypoxic and the oxygenation increases at the base of the villi. IBD results in heightened hypoxia throughout the mucosa. Hypoxia signals through a well-conserved family of transcription factors, where hypoxia-inducible factor (HIF)-1α and HIF-2α are essential in maintaining intestinal homeostasis. In inflamed mucosa, HIF-1α increases barrier protective genes, elicits protective innate immune responses, and activates an antimicrobial response through the increase in β-defensins. HIF-2α is essential in maintaining an epithelial-elicited inflammatory response and the regenerative and proliferative capacity of the intestine following an acute injury. HIF-1α activation in colitis leads to a protective response, whereas chronic activation of HIF-2α increases the pro-inflammatory response, intestinal injury, and cancer. In this mini-review, we detail the role of HIF-1α and HIF-2α in intestinal inflammation and injury and therapeutic implications of targeting HIF signaling in IBD.