Constitutive androstane receptor regulates the intestinal mucosal response to injury
Constitutive androstane receptor regulates the intestinal mucosal response to injury
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DOI：
10.1111/bph.13787
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发表时间：
2017-06-01
影响因子：
7.3
通讯作者：
Hirota, Simon A.
中科院分区：
文献类型：
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作者：
Hudson, Grace M.;Flannigan, Kyle L.;Hirota, Simon A.
炎症性肠病(IBD)包括克罗恩病(CD)和溃疡性结肠炎(UC)，其发病机制涉及遗传易感个体及其微生物群和环境因素之间的异常相互作用。异种受体表达和功能的改变与IBD风险增加相关。在这里，我们评估了构成雄烷受体(CAR)，一种与孕烷X受体密切相关的异源受体在调节肠粘膜自身稳定中的作用。实验方法评估了CD和UC患者的肠粘膜活检组织中CAR的表达，以及暴露于葡聚糖硫酸钠(DSS；饮用水中3.5%w/v)引起肠道炎症和组织损伤的C57/BL6小鼠。CAR缺乏的小鼠暴露在DSS中，并评估粘膜愈合情况。体外观察CAR对创面愈合的调节作用。使用啮齿动物CAR激动剂3，3，5，5-tetrachloro-1，4-bis(pyridyloxy)benzene(TCPOBOP)评估CAR激活的治疗潜力。这在我们的DSS研究中重现，其中CAR在结肠炎小鼠中的表达减少。在DSS暴露后，CAR缺乏的小鼠表现出愈合减少。在体外，CAR的激活通过促进细胞迁移促进了肠上皮伤口的愈合。最后，用TCPOBOP治疗小鼠，在诱导结肠炎后，促进粘膜愈合。结论和意义我们的结果支持在肠道炎症过程中异物感觉改变的观点，并提示CAR激活可能被证明在促进IBD患者的粘膜愈合方面是有效的。
Background and PurposeThe pathogenesis of the inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), involves aberrant interactions between a genetically susceptible individual, their microbiota and environmental factors. Alterations in xenobiotic receptor expression and function are associated with increased risk for IBD. Here, we have assessed the role of the constitutive androstane receptor (CAR), a xenobiotic receptor closely related to the pregnane X receptor, in the regulation of intestinal mucosal homeostasis.Experimental ApproachCAR expression was assessed in intestinal mucosal biopsies obtained from CD and UC patients, and in C57/Bl6 mice exposed to dextran sulphate sodium (DSS; 3.5% w/v in drinking water) to evoke intestinal inflammation and tissue damage. CAR-deficient mice were exposed to DSS and mucosal healing assessed. Modulation of wound healing by CAR was assessed in vitro. The therapeutic potential of CAR activation was evaluated, using 3,3,5,5-tetrachloro-1,4-bis(pyridyloxy)benzene (TCPOBOP), a selective rodent CAR agonist.Key ResultsCAR expression was reduced in CD and UC samples, compared with expression in healthy controls. This was reproduced in our DSS studies, where CAR expression was reduced in colitic mice. CAR-deficient mice exhibited reduced healing following DSS exposure. In vitro, CAR activation accelerated intestinal epithelial wound healing by enhancing cell migration. Lastly, treating mice with TCPOBOP, following induction of colitis, enhanced mucosal healing.Conclusion and ImplicationsOur results support the notion that xenobiotic sensing is altered during intestinal inflammation, and suggest that CAR activation may prove effective in enhancing mucosal healing in patients with IBD.