Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke
Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke
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DOI：
10.1161/strokeaha.115.008989
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发表时间：
2015-11-01
期刊：
影响因子：
8.3
通讯作者：
Meisel, Andreas
中科院分区：
文献类型：
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作者：
Engel, Odilo;Akyuez, Levent;Meisel, Andreas
背景和目的暂时免疫抑制已被确定为急性中枢神经系统损伤后发生肺炎的主要危险因素。虽然交感神经系统的过度激活先前被证明可以介导中风后全身细胞免疫反应的抑制，但副交感神经胆碱能抗炎途径在肺抗菌防御中的作用仍然难以捉摸。方法采用小鼠大脑中动脉闭塞模型，观察副交感神经系统对脑卒中后免疫抑制的影响。我们使用遥测、迷走神经切断术、α7烟碱乙酰胆碱受体缺陷小鼠和拟副交感神经（尼古丁，PNU282987）测量和调节副交感神经活动的心率变异性测量。结果实验小鼠脑卒中后副交感神经活动迅速增加。迷走神经切断或α7烟碱乙酰胆碱受体缺陷小鼠对胆碱能信号的抑制可逆转肺免疫低反应性，预防脑卒中后肺炎。利用骨髓嵌合小鼠和离体原代细胞对α7烟碱乙酰胆碱受体在不同肺细胞中的作用进行体内和离体研究表明，巨噬细胞和肺泡上皮细胞都是肺中胆碱能抗炎信号的主要靶细胞。结论胆碱能通路在急性中枢神经系统损伤后肺部感染的发生发展中起关键作用。
Background and PurposeTemporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive.MethodsThe middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor–deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity.ResultsHere, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor–deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic anti-inflammatory signaling in the lung.ConclusionsThus, cholinergic pathways play a pivotal role in the development of pulmonary infections after acute central nervous system injury.