Th17/Treg平衡在大气细颗粒物质（PM2.5）诱导的气道炎症中的作用研究

PM2.5 is related to the morbidity and mortality of chronic inflammatory diseases, which is difficult to prevent and treat,but the exact mechanism is not clear. The imbalance of body immune microenvironment is one of the important mechanism of inflammtory responses induced by PM2.5. On the basis of previous studies, the project intends to take Th17/Treg balance as a focus, explore the role of Th17 and Treg in inflammatory responses induced by PM2.5 by observing the different expression; further explore the mechanism of Th17/Treg differentiation imbalance induced by PM2.5 by inducing differentiation in vitro and understand the regulatory role of Treg cells to Th cells through the intervention. We would like to clarify the interaction and regulation mechanism of Th17 and Treg in airway inflammation induced by PM2.5, and to further study the immunological mechanisms of airway inflammatory responses and adverse health effects caused by PM2.5. In order to explain the nature of health effects on air pollution, and to explain the relationship between air pollution and some chronic respiratory inflammatory diseases, the project should be early execute, so as to provide scientific evidence to prevent and treat related diseases caused by air pollution, also provide a theoretical basis to early and effictive intervent those diseases.

PM2.5与慢性炎症性疾病的发病和死亡密切相关，确切机制不明，造成防治困难。体内免疫微环境平衡网络的失衡是PM2.5造成机体炎症反应的重要机制。在前一资助项目的基础上，本项目拟以在慢性炎症性疾病中起重要作用的Th17/Treg平衡为切入点，通过人体及动物模型观察PM2.5暴露对Th17/Treg表达的影响，研究其上下游调节机制及与Th1/Th2等其他微免疫平衡的关系， 通过体外诱导分化及干预，阐明这些变化在PM2.5致病作用的因果关系。从而研究Th17和Treg在PM2.5诱导的炎症中的作用，阐明Th17和Treg在PM2.5诱导的气道炎症中的相互作用及调节机制，深入研究PM2.5导致气道炎症及负面健康效应的免疫学机制。从而解释大气污染健康效应的本质，解释某些慢性呼吸系统炎症性疾病与大气污染的关系，为大气污染及其相关疾病的宏观防治策略提供科学证据，对大气污染相关疾病早期有效干预提供依据。

PM2.5导致气道炎症及负面健康效应的免疫学机制不清，本项目拟以Th17/Treg平衡为切入点，从在体研究、体外研究和人群研究三个方面，深入探讨PM2.5通过介导Th17/Treg失衡所致气道炎症损伤的机制。首先，在体研究中，我们建立PM2.5暴露小鼠模型，对小鼠进行肺功能检测，肺组织病理分析和电镜观察。通过免疫组化、多因子检测等方法检测气道上皮和BALF中炎症因子水平，通过流式测定小鼠脾脏Th17和Treg细胞比例；对PM2.5暴露小鼠，给予木犀草素干预后观察疗效。应用mircoRNA基因芯片和realtime-PCR的方法检测了与Th1/Th2平衡相关的因子IL-4/IFN-γ，以及相关的mircoRNA谱。结果显示PM2.5暴露的小鼠肺脏阻力增大。气道上皮细胞和BALF中多种炎症因子如IL-17、TGF-β、IL-4和IL-6表达上调；Th17/Treg细胞百分比上调。提示PM2.5暴露后发生Th17/Treg分化失衡并向Th17激活的方向偏移。而给予木犀草素，可明显减轻PM2.5暴露后小鼠炎症损伤及Th17/Treg偏移。PM2.5慢性暴露主要引起Th17/Treg失衡，而PM2.5急性暴露主要引起Th1/Th2失衡，偏向Th1方向；miRNA-691, -181a, -146a, -146b, -21a-3p, -21a-5p ,-340参与了Th1/Th2分化失衡。体外研究中，建立PM2.5细胞染毒模型。检测培养上清中TGF-β水平，电镜下观察自噬小体，给予TGF-β抑制剂后，检测自噬相关蛋白LC3的水平。结果显示PM2.5可通过上调TGF-β诱导自噬; PI3K/Akt/mTOR为其重要通路。在人群研究方面，我们利用2008年HEART研究获得的样本及数据；以及利用时间序列和病例交叉逻辑回归模型，探讨了大气污染动态变化与人群肺部炎症反应关系。结论：PM2.5的暴露可导致小鼠气道炎症，肺脏阻力升高，Th17/Treg分化失衡并向Th17激活的方向偏移。木犀草素能通过抑制炎症因子分泌、减轻Th17/Treg失衡从而发挥免疫调节作用。PM2.5暴露可通过TGF-β因子诱导自噬从而与Th17/Treg分化失衡相关。miRNA 谱参与了Th1/Th2的分化失衡。PM2.5水平与健康人群肺功能动态变化相关，同时也是影响急诊就诊人次增加的重要因素。

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