Hudson Grace M, Flannigan Kyle L, Erickson Sarah L, Vicentini Fernando A, Zamponi Alexandra, Hirota Christina L, Alston Laurie, Altier Christophe, Ghosh Subrata, Rioux Kevin P, Mani Sridhar, Chang Thomas K, Hirota Simon A
Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada.
Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Canada.
Br J Pharmacol. 2017 Jun;174(12):1857-1871. doi: 10.1111/bph.13787. Epub 2017 Apr 19.
The 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.
CAR 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.
CAR 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.
Our 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.
炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC），其发病机制涉及基因易感性个体、微生物群和环境因素之间的异常相互作用。外源性物质受体表达和功能的改变与IBD风险增加相关。在此，我们评估了组成型雄烷受体（CAR），一种与孕烷X受体密切相关的外源性物质受体，在调节肠道黏膜稳态中的作用。
在从CD和UC患者获取的肠道黏膜活检组织中，以及在暴露于葡聚糖硫酸钠（DSS；饮用水中3.5% w/v）以引发肠道炎症和组织损伤的C57/Bl6小鼠中评估CAR表达。使CAR缺陷小鼠暴露于DSS并评估黏膜愈合情况。在体外评估CAR对伤口愈合的调节作用。使用3,3',5,5'-四氯-1,4-双（吡啶氧基）苯（TCPOBOP），一种选择性啮齿动物CAR激动剂，评估CAR激活的治疗潜力。
与健康对照中的表达相比，CD和UC样本中CAR表达降低。这在我们的DSS研究中得到重现，其中结肠炎小鼠中CAR表达降低。CAR缺陷小鼠在暴露于DSS后愈合能力降低。在体外，CAR激活通过增强细胞迁移加速肠道上皮伤口愈合。最后，在诱导结肠炎后用TCPOBOP治疗小鼠可增强黏膜愈合。
我们的结果支持这样的观点，即肠道炎症期间外源性物质感知发生改变，并表明CAR激活可能在增强IBD患者的黏膜愈合方面证明有效。
