Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice
Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice
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DOI：
10.1111/nmo.13501
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发表时间：
2019-03-01
影响因子：
3.5
通讯作者：
Wehner, Sven
中科院分区：
文献类型：
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作者：
Hong, Gun-Soo;Zillekens, Anne;Wehner, Sven
背景胆碱能抗炎通路包括传入感觉神经元感知外周炎症和反射激活传出迷走神经活动以调节炎症。这一通路的激活被证明可以减少炎症反应，改善啮齿动物术后肠梗阻(POI)和脓毒症的预后。在这里，我们测试了无创性耳部电刺激(TVNS)是否影响POI或内毒素血症模型的炎症。方法采用肠道操作(IM)诱导POI或内毒素血症诱导小鼠出现内毒素血症，分别在刺激前后进行TVNS或假刺激。一些动物在手术前接受了右侧颈迷走神经切断术。免疫组织化学方法检测c-fos(+)细胞，分析孤束核(NTS)和迷走神经背侧运动核(DMV)神经元的激活情况。观察IM后不同时间点IL-6、MCP-1、IL-1β的基因和蛋白表达，以及白细胞浸润和胃肠道转运情况。在注射脂多糖3小时后检测血清IL-6、TNF-α和IL-1β水平。结果TVNS激活NTS和DMV，减少肠道细胞因子的表达，减少白细胞向被操纵肠段的募集，改善IM后的胃肠传输。TVNS还能减少内毒素血症所致的IL-6和TNF-α的释放。切断迷走神经后，TVNS对POI和内毒素血症的保护作用消失。结论TVNS可预防肠道和全身炎症。DMV的激活表明刺激tVNS的传出中枢回路的传入，而tVNS的有益效应依赖于完整的迷走神经。TVNS可能成为治疗POI的一种非侵入性方法。
Background The cholinergic anti-inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non-invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. Methods Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c-fos(+) cells. Gene and protein expression of IL-6, MCP-1, IL-1 beta as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL-6, TNF alpha, and IL-1 beta serum levels were analyzed 3 hours after lipopolysaccharide administration. Results tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia-induced IL-6 and TNF-alpha release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. Conclusion tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non-invasive approach for treatment of POI.