Targeting α-7 Nicotinic Acetylcholine Receptor in the Enteric Nervous System A Cholinergic Agonist Prevents Gut Barrier Failure after Severe Burn Injury
Targeting α-7 Nicotinic Acetylcholine Receptor in the Enteric Nervous System A Cholinergic Agonist Prevents Gut Barrier Failure after Severe Burn Injury
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DOI：
10.1016/j.ajpath.2012.04.005
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发表时间：
2012-08-01
影响因子：
6
通讯作者：
Coimbra, Raul
中科院分区：
文献类型：
--
作者：
Costantini, Todd W.;Krzyzaniak, Michael;Coimbra, Raul
我们之前已经在严重烧伤模型中证明迷走神经刺激可以防止肠屏障丧失，在严重烧伤模型中，损伤与肠紧密连接蛋白的表达减少和定位改变有关。α -7烟碱乙酰胆碱受体（α -7 nAchR）已被证明是迷走神经调节全身炎症反应所必需的，但α -7 nAchR在介导肠道保护中的作用尚不清楚。我们假设α -7 nAchR可能存在于胃肠道中，并且α -7 nAchR的药物激动剂治疗可以防止烧伤引起的肠道屏障损伤。研究了胆碱能激动剂在损伤后30分钟腹腔注射尼古丁对肠屏障完整性的影响。通过测定对4-kDa异硫氰酸-葡聚糖荧光素的通透性和检测肠紧密连接蛋白occludin和ZO-1的表达和定位变化来检测肠屏障的完整性。损伤后注射尼古丁可预防烧伤引起的肠通透性，限制肠组织损伤。在单独烧伤的动物中观察到，尼古丁治疗可以防止occludin和ZO-1的表达减少和定位改变。明确迷走神经、肠神经系统和肠上皮之间的相互作用可能会导致靶向治疗的发展，旨在减少严重损伤后肠道屏障功能衰竭和肠道炎症。（中华病理学杂志，2012,181:478-486 http://dx.doi.org/10.1016/j.ajpath.2012.04.005）
We have previously shown that vagal nerve stimulation prevents intestinal barrier loss in a model of severe burn injury in which injury was associated with decreased expression and altered localization of intestinal tight junction proteins. alpha-7 Nicotinic acetylcholine receptor (alpha-7 nAchR) has been shown to be necessary for the vagus nerve to modulate the systemic inflammatory response, but the role of alpha-7 nAchR in mediating gut protection remained unknown. We hypothesized that alpha-7 nAchR would be present in the gastrointestinal tract and that treatment with a pharmacological agonist of alpha-7 nAchR would protect against burn-induced gut barrier injury. The effects of a pharmacological cholinergic agonist on gut barrier integrity were studied using an intraperitoneal injection of nicotine 30 minutes after injury. Intestinal barrier integrity was examined by measuring permeability to 4-kDa fluorescein isothiocyanate-dextran and by examining changes in expression and localization of the intestinal tight junction proteins occludin and ZO-1. Nicotine injection after injury prevented burn-induced intestinal permeability and limited histological gut injury. Treatment with nicotine prevented decreased expression and altered localization of occludin and ZO-1, as seen in animals undergoing burn alone. Defining the interactions among the vagus nerve, the enteric nervous system, and the intestinal epithelium may lead to development of targeted therapeutics aimed at reducing gut barrier failure and intestinal inflammation after severe injury. (Am J Pathol 2012, 181:478-486 http://dx.doi.org/10.1016/j.ajpath.2012.04.005)