溶血磷脂酰胆碱调节肺巨噬细胞M2型极化参与哮喘气道重塑的机制研究

Airway remodeling is a major cause of death among patients with severe asthma. It is well recognized that M2 polarization of lung macrophages leads to subepithelial fibrosis, which is a crucial component of airway remodeling in asthma. Recently, lots of studies have been undertaken to investigate the molecular mechanisms underlying the initiation and inhibition of M2 polarization. Our previous research has demonstrated that lysophosphatidylcholine (lysoPC) played a critical role in asthma airway inflammation and hyperreactivity for the first time, but its role in airway remodeling is unknown. In the preliminary experiment, we found lysoPC could regulate the mice lung macrophages polarization to M2 type. Moreover, its receptor and downstream signal including STAT6 and IRF4 were involved in M2 polarization. We hypothesized that lysoPC might participate in the airway remodeling through regulating the lung macrophages polarization to M2 type in asthma. By using gene knock-out macrophages and a mouse model of asthma, we plan to investigate the capacity and molecular mechanism by which lysoPC regulates lung macrophages polarization in the development of airway remodeling. Clarification of the role of lysoPC in asthma will potentially improve the prevention and management of the disease.

气道重塑是导致重症哮喘患者死亡的主要原因之一。肺巨噬细胞向M2型极化，致气道上皮下纤维化是哮喘气道重塑主要机制之一，寻找巨噬细胞向M2型极化的启动机制和早期阻断办法，是目前哮喘研究的热点。我们前期研究证实溶血磷脂酰胆碱（lysoPC）是参加哮喘气道炎症和气道高反应性的关键物质，但其对哮喘气道重塑的作用尚不明确。我们预实验发现，lysoPC调节小鼠肺巨噬细胞向M2型极化，具体机制尚不明确，可能与其受体及下游信号STAT6、IRF4有关，推测lysoPC可能通过调节肺巨噬细胞M2型极化参与哮喘气道重塑。本项目拟以基因敲除的巨噬细胞和哮喘小鼠为研究对象，从体内和体外探索lysoPC调节肺巨噬细胞M2型极化，参与哮喘气道重塑的可能机制和相关信号途径，为进一步阐明哮喘气道重塑的机制和寻找新的治疗靶点提供实验依据。

肺巨噬细胞向M2型极化，致气道上皮下纤维化是哮喘气道重塑主要机制之一。本课题拟研究溶血磷脂酰胆碱（lysoPC）调节肺巨噬细胞M2型极化，参与哮喘气道重塑的可能机制和相关信号途径。本课题在细胞实验研究中，发现lysoPC可能诱导巨噬细胞-成纤维细胞转换，参与气道重塑。但在哮喘小鼠的动物模型中未能观察到上述现象。因此，课题组调整研究方向，通过查阅文献发现髓样细胞触发受体2（Trem2），具有潜在调节巨噬细胞M2型极化作用，课题组观察到哮喘患者肺M2型巨噬细胞表达Trem2，表达水平高于健康对照组。IL-4刺激小鼠BMDM细胞使其M2型极化后，用Trem2-siRNA转染BMDM，后者表达M2型细胞因子水平下降。将包载Trem2-siRNA阳离子脂质体的纳米粒，注入哮喘小鼠气道，下调气道内Trem2表达，干预后哮喘小鼠BALF中炎性细胞总数及分类计数、M2型巨噬细胞因子、Th2炎性细胞因子表达水平下降，气道炎症得到改善。研究结果为Trem2作为哮喘潜在的新治疗靶点提供理论依据和实验数据。COVID-19期间，实验室工作停滞，本课题组及时展开COVID-19的临床研究，针对武汉三家定点医院“新冠肺炎”的肿瘤患者的临床特征进行回顾性分析，发现新冠肺炎诊断2周内放化疗及入院时CT影像肺实变，是肿瘤患者发生临床严重事件的独立危险因素。论著发表后被多次引用，为严重疫情下肿瘤患者的临床决策提供了重要的研究数据。另一项针对患COVID-19的糖尿病患者的回顾性研究，发现血cTNI水平的升高，与患者临床严重事件的发生率显著相关。