α7 烟碱型乙酰胆碱受体在肥胖症肺部炎症反应中肺泡巨噬细胞的表达及调控机制研究

Obesity is a metabolic disease that increases the risk of multiple lung disorders. It is well-known that chronic inflammation plays an important role in the pathogenesis of obesity. Particularly,α7 nicotinic acetylcholine receptor (α7 nAChR) mediates cholinergic anti-inflammatory signaling pathways that inhibit synthesis of cytokines and control inflammatory responses. Meanwhile alveolar macrophages play main roles in CAP, but whether it is involved in obesity and inflammation in lung is not clear. Our preliminary data suggest that the expression of ATII α7 nAChR in obese mice was decreased and the effect of nicotine on initiating cell depolarization was decreased in ATII in obese mice. Therefore, we hypothesize that the expression and function of α7 nAChR in alveolar macrophages are reduced in obese mice, which aggravate the decreased inflammation inhibition pathways and the enhanced pro-inflammatory pathways. In this project, we will investigate the expression of α7 nAChRs and the relationship between the expression of α7 nAChR and lung inflammation in alveolar macrophages by using patch-clamp recordings and molecular techniques, and the mechanisms by using alveolar macrophages and adipocytes co-culture system.

肥胖症是一种代谢性疾病，肥胖增加多种肺部疾病发病风险。慢性炎症在肥胖症的发病机制中起重要作用，α7烟碱型乙酰胆碱受体（α7 nAChR）介导的“胆碱能抗炎通路(CAP)”抑制细胞因子的合成，控制炎症反应。而肺泡巨噬细胞是CAP的主要参与者，但其是否参与肥胖症肺部炎症及其机制尚不清楚。我们前期研究显示肥胖小鼠肺部炎症反应增强，肺泡II型上皮细胞(ATII) α7 nAChR在肥胖小鼠中表达下调,烟碱对ATII刺激自发放电活动较正常小鼠减弱。因此我们推测：肥胖症肺泡巨噬细胞α7 nAChR的表达或功能下调，导致炎症抑制通路功能下降，促炎通路炎症介质产生增加。本项目拟通过肥胖小鼠和基因敲除小鼠模型，采用膜片钳技术和分子生物学的方法研究肥胖症小鼠肺泡巨噬细胞α7 nAChR的表达与肺部炎症的关系，并通过原代肺泡巨噬细胞与脂肪细胞共培养体系研究脂肪细胞对肺泡巨噬细胞α7 nAChR的表达及影响机制。

肥胖症是一种代谢性疾病，肥胖增加多种肺部疾病发病风险。慢性炎症在肥胖症的发病机制中起重要作用，α7烟碱型乙酰胆碱受体（α7 nAChR）介导的“胆碱能抗炎通路(CAP)”抑制细胞因子的合成，控制炎症反应。而肺泡巨噬细胞是CAP的主要参与者，但其是否参与肥胖症肺部炎症及其机制尚不清楚。本课题按计划基本上完成了既定目标，探讨了α7 nAChR介导的通路CAP在肥胖症肺部炎症中的作用及机制。首先我们研究发现高脂饮食诱导肥胖小鼠肺部α7 nAChR表达水平降低，同时肥胖受试者和肥胖小鼠肺内炎症反应增强，之后通过体外实验表明α7 nAChR通过介导CAP通路调控肺巨噬细胞代谢性炎症。本课题进一步研究肥胖小鼠在脂多糖诱导急性肺损伤“二次打击”后，肺组织以及肺泡巨噬细胞、肺间质巨噬细胞α7nAChR表达水平显著降低，同时通过α7 nAChR激动剂、拮抗剂以及迷走神经切断等动物水平体内干预，发现肥胖小鼠α7nAChR介导的抗炎功能被弱化，进而诱导加重肺部炎症，本研究从神经源性免疫调节方向揭示了α7nAChR可能是肥胖症急性肺损伤的潜在干预靶点。本课题根据前期肥胖小鼠肺单细胞转录组测序数据的生信分析，延伸探索了肥胖症肺巨噬细胞STING的表达增强及其参与调控肥胖小鼠肺巨噬细胞代谢性炎性激活的作用机制，为靶向STING在肥胖症肺部炎症的临床应用提供重要依据。