链接蛋白MyD88调控PM2.5诱导急性气道炎症的分子机制

PM2.5 rising is status quo in our country. People look forward to control the air pollution as soon as possible. But whether PM2.5 can cause acute lung inflammation? How is the dose-effect relationship and time-effect relationship? What is the pathological molecular mechanisms and control strategies? At current international reports, though the published papers about air pollution epidemiology investigation are more, the molecular basis in PM2.5-induced acute lung inflammation is less. Our preliminary experiment results have proved the inhaled PM2.5 can lead to the activation of TLR4 and MyD88 in the lung tissue. MyD88 inhibitor can significantly reduce PM2.5-induced infiltration of neutrophils and macrophages, and the production of inflammatory cytokines in the lung tissue. These results reveal that the MyD88 is an important role of lung inflammation caused by PM2.5. This project will study MyD88 as a critical potential signaling target in PM2.5-caused acute lung inflammation. We will apply the MyD88 knockout mice, MyD88 specific inhibitors, siRNA as research tools and molecular pharmacology methods, and explore the regulating mechanism of MyD88 signaling in the process of PM2.5-induced macrophages autophagy. This study will define the molecular basis of the MyD88 signaling in autophagy. It is very important significance to understand and control lung disease caused by the air pollution.

PM2.5攀高是我国的现状，治理空气污染是广大民众的期盼。但PM2.5是否可引起急性肺部炎症？其量效-时效关系如何？其病理分子机制和防治策略如何？虽然有关空气污染流行病学调查研究的报道较多，但关于PM2.5引起急性肺部炎症的分子机制的研究较少。我们的预实验已证明吸入PM2.5能导致肺组织中TLR4和MyD88的激活，MyD88抑制剂能显著减少PM2.5所导致的中性粒细胞和巨噬细胞在肺组织的浸润和炎症介质的产生，揭示MyD88在PM2.5所致肺部炎症中的重要地位。本研究将MyD88作为影响PM2.5引起急性肺部炎症的潜在信号，采用MyD88基因敲除小鼠、MyD88特异性抑制剂、siRNA等工具和分子药理学方法，通过离体和整体实验探索MyD88信号在PM2.5引起肺巨噬细胞自噬过程中的调节机制，阐明MyD88信号在自噬中的分子基础。这项研究对理解和防治空气污染导致的肺脏疾病具有非常重要的意义。

PM2.5攀高是我国的现状，治理空气污染是广大民众的期盼。但PM2.5是否可引起急性肺部炎症？目前其相关的分子机制研究亦较少。我们的预实验已证明吸入PM2.5能导致肺组织中TLR4和MyD88的激活，MyD88抑制剂能显著减少PM2.5所导致的中性粒细胞和巨噬细胞在肺组织的浸润和炎症介质的产生，揭示MyD88在PM2.5所致肺部炎症中的重要地位。本研究通过整体和离体实验探索MyD88信号在PM2.5引起肺巨噬细胞自噬过程中的调节机制。离体试验结果显示：1）PM2.5增加巨噬细胞TLR4和MyD88蛋白表达。2）PM2.5上调LC3BII/I比例、增加Beclin1表达、降低SQSTM1/p62表达，促进细胞自噬。3）抑制MyD88能降低PM2.5诱导的巨噬细胞IL-1β、TNF-α、IL-6表达，降低巨噬细胞自噬。整体试验结果显示：1）MyD88抑制剂能降低PM2.5诱导的肺部炎症小鼠气道高反应性。2）MyD88抑制剂降低小鼠肺部中性粒细胞和巨噬细胞浸润，降低粘液分泌。3）MyD88抑制剂减少IL-1β、TNF-α、IL-6分泌。4）降低Beclin1表达、上调SQSTM1/p62表达，抑制自噬。MyD88抑制剂的抗肺部炎症作用可能是通过Erk、AKT、NF-κB起作用。上述结果表明MyD88是用于防治PM2.5诱导的肺部炎症的潜在靶点。