迷走神经刺激通过增加内源性脂氧素产生调控急性肺损伤炎症消退过程

Numerous evidences have placed exaggerated and dysregulated inflammation as the fundamental factor for the onset and progression of acute lung injury(ALI). Alveolar machrophages(AMs), which are essential to innate immunity and host defense, could be activated rapidly in response to pathogens introduction and mechanical injury to cells or tissue. AMs dynamically alter their phenotype and function during early inflammatory and late resolution phases, playing distinct roles. Cholinergic anti-inflammatory pathway, primarily composed of efferent activity in the vagus nerve and neurotransmitter acetylcholine(Ach), has an crucial role in preventing systemic inflammation, which is dependent on α7nAChR on macrophages. Lipoxins, a group of endogenous lipid mediators that have anti-inflammatory and pro-resolution properties, ameliorates pulmanory inflammtion when used in animal models. Hence, we speculate that reduced production of endogenous lipoxins leads to defective resolution of acute inflammation in ALI, resulting in excess inflammatory response and unfavorable outcomes. Vagal nerve stimulation augments the formation of lipoxins, followed by promoting M2 polarization of AMs, eventually contributing to inflammatory resolution. For current study, we proposed to establish an ALI model in mice, and utilize methods including vagal nerve electrical stimulation, cDNA Microarray, primary mice AMs culture and flow cytometry, to confirm our hypothesis. This study, however, may provide new insights into the cause of ALI and potential therapeutic targets for it.

急性肺损伤（ALI）发生的根本原因是肺内过度性、失控性炎症反应，肺泡巨噬细胞在机体感染或受到损伤时迅速激活，在炎症反应的起始、发展和消退过程中，发生不同表型之间的转化，调节炎症反应。胆碱能抗炎通路由迷走神经及其释放的递质乙酰胆碱为主构成，可以调节全身炎症反应,此效应依赖于巨噬细胞表明的烟碱样受体α7nAChR。脂氧素是重要的促炎症消退介质，外源性给予即可改善肺部炎症反应。因此，我们推测，ALI时，内源性脂氧素生成不足致使炎症消退障碍,从而导致肺脏炎症反应失控，造成不良预后；迷走神经刺激可以激活内源性脂氧素生成，促进肺泡巨噬细胞向M2型极化，促进ALI炎症消退。我们拟建立小鼠ALI模型，应用迷走神经电刺激、基因芯片、原代小鼠肺泡巨噬细胞培养、流式细胞检测等技术，从整体-组织-细胞-分子层面，依次证明我们的假说。此研究将为急性肺损伤的治疗提供新思路和新靶点。

消退障碍是急性肺损伤（ALI）或急性呼吸窘迫综合征（ acute respiratory distress syndrome, ARDS）的主要病理学特点之一。内源性的胆碱能抗炎通路（cholinergic anti-inflammatory pathway, CAP）通过迷走神经末梢释放的乙酰胆碱（ acetylcholine, ACh）靶向激活α7烟碱型乙酰胆碱受体(α7nAChR)，可缓解类风湿性关节炎等炎症反应。肺上皮细胞和肺泡巨噬细胞高表达 α7nAChR受体，且迷走神经刺激可促进内源性消退介质（脂氧素）生成。由此，本项目围绕“刺激迷走神经，内源性促进炎症消退，减轻肺损伤”的假设，进行了以下研究：不同强度的电压进行迷走神经电刺激，或α7nAChR激活，可通过调节肺泡巨噬细胞STAT信号通路，促进肺部炎症消退，减轻 ARDS 模型小鼠的肺损伤；进一步研究证实，α7nAChR受体激活肺泡巨噬细胞，STAT6磷酸化水平或PPARγ核转位增加，促使其向炎症消退表型（M2）转化。