ARYL HYDROCARBON RECEPTOR ACTIVATION IN INTESTINAL OBSTRUCTION AMELIORATES INTESTINAL BARRIER DYSFUNCTION VIA SUPPRESSION OF MLCK-MLC PHOSPHORYLATION PATHWAY
ARYL HYDROCARBON RECEPTOR ACTIVATION IN INTESTINAL OBSTRUCTION AMELIORATES INTESTINAL BARRIER DYSFUNCTION VIA SUPPRESSION OF MLCK-MLC PHOSPHORYLATION PATHWAY
复制标题
肠梗阻中芳基烃受体的激活通过抑制 MLCK-MLC 磷酸化途径改善肠屏障功能障碍
DOI：
10.1097/shk.0000000000000594
复制
发表时间：
2016-09-01
期刊：
影响因子：
3.1
通讯作者：
Yang, Hua
中科院分区：
文献类型：
--
作者：
Han, Bin;Sheng, Baifa;Yang, Hua
背景：越来越多的证据表明，在炎症性肠病患者和小鼠模型中，芳香烃受体在维持肠屏障功能方面发挥着重要作用。肠梗阻(IO)是一种以严重的肠屏障功能障碍为特征的临床急症，AhR在IO的发病机制中是否起作用尚不清楚，但意义重大。方法：雄性C57BL/6小鼠接受IO，给予AhR内源性激动剂6-甲酰吲哚[3，2-b]咔唑(FICZ)治疗或不治疗。24 h后取肠组织，分别在体外无缺氧或无缺氧的情况下给予FICZ处理或不处理。结果：IO和低氧诱导的小鼠CaCO-2模型小鼠肠黏膜损伤明显减轻，肠通透性明显高于对照组(P<0.05)。在此条件下，AhR的活性较低，闭合带-1(ZO-1)的荧光消失。肌球蛋白轻链激酶(MLCK)和磷酸化MLC(PMLC)的表达增加，表明该通路是开放的。然而，FICZ治疗导致紧密连接蛋白ZO-1的滞留，减轻了肠道通透性的增加，并减轻了上皮损伤。在体外，AhR小干扰RNA抑制AhR使MLCK-pMLC信号通路解堵，并抑制ZO-1的蛋白表达。结论：AHR激活可通过抑制MLCK-pMLC信号通路改善IO所致的上皮屏障功能障碍，提示AhR激动剂可能是一种合适的治疗手段。
Background: Accumulating evidence suggests that the aryl hydrocarbon receptor (AhR) plays an important role in the maintenance of the function of the intestinal barrier in patients with inflammatory bowel disease and in mouse models. Intestinal obstruction (IO) is a clinical emergency consisting of severe dysfunction of intestinal barrier function, and whether AhR plays a role in the pathogenesis of IO remains unknown but would be highly significant. Methods: Male C57BL/6 mice were subjected to IO and either treated with AhR endogenous agonist 6-formylindolo [3, 2-b] carbazole (FICZ) or left untreated. Intestinal tissue was harvested after 24 h. Correspondingly, Caco-2 monolayers were treated with FICZ in the absence or presence of hypoxia in vitro or left untreated. The cells were used after 12 h. Results: Damage to the intestinal mucosa was anabatic and intestinal permeability was significantly higher in murine IO and hypoxia-induced Caco-2 models than in controls. Under these conditions the activity of AhR was lower and the fluorescence of zonula occludens-1 (ZO-1) was absent. The increased expression of myosin light chain kinase (MLCK) and phosphorylated MLC (pMLC) indicated that this pathway was open. However, treatment with FICZ caused retention of the tight junction protein ZO-1, alleviated the increase of intestinal permeability, and mitigated epithelial injury. Depletion of AhR by AhR small interfering RNA facilitated the unblocking of the MLCK-pMLC signaling pathway and repressed the protein expression of ZO-1 in vitro. Conclusion: AhR activation can ameliorate epithelial barrier dysfunction induced by IO through the suppression of MLCK-pMLC signaling, suggesting that AhR agonist may be a suitable means of addressing this condition.