肺泡巨噬细胞对PM10/PM2.5所致肺部炎症Th免疫应答的调控及机制研究

PM10 and PM2.5 are the main particulate air pollutants whose aerodynamic diameter is not more than 10 micron or 2.5 micron. Lung inflammation plays an important role in many kinds of respiratory disease induced by PM10/PM2.5. However, the lung inflammation induced by different sources of PM10/PM2.5 is usually different. The mechanism of the immunological modulation during this pathology process is still not clearly demonstrated. After PM10/PM2.5 exposure, alveolar macrophages will secreting a lot of pro-inflammatory cytokines. Meanwhile, as a powerful antigen presenting cells (APC), the alveolar macrophages will activate CD4+T lymphocytes and start the Th immune response. Nevertheless, the role of alveolar macrophages in regulating PM10/PM2.5-induced different lung inflammation is unclear. The aim of our project is to observe the effect of PM10/PM2.5 on respiratory system by establishing an acute mouse model exposed to PM10/PM2.5; to illustrate the regulatory mechanism of alveolar macrophages on the Th immune response in lung inflammation induced by PM10/PM2.5 from different sources. It is believed that if we demonstrated the regulatory mechanism of alveolar macrophages on Th immune responses successfully, the powerful experimental and theoretical foundation will be provided to help delaying and inhibiting the development of PM10/PM2.5 induced lung inflammation and other disease.

PM10/PM2.5即空气中直径小于10微米或2.5微米的颗粒物，是主要空气颗粒污染物。肺部炎症在PM10/PM2.5诱发的多种呼吸系统疾病中起着重要的作用。但不同来源的PM10/PM2.5引起的肺部炎症通常不同，目前此类炎症病理过程的免疫调控机制尚未十分清楚。研究表明，PM10/PM2.5暴露后，肺泡巨噬细胞在释放大量炎性因子的同时，作为一种功能强大的抗原提呈细胞，激活CD4+T淋巴细胞，启动Th免疫进程。但巨噬细胞在PM10/PM2.5所致肺部炎症免疫进程中的确切调控机制尚不清楚。本研究拟通过建立巨噬细胞消除小鼠PM10/PM2.5暴露模型并通过体外实验，从细胞和分子水平探讨巨噬细胞在PM10/PM2.5诱发肺部炎症Th应答中的作用及免疫调控机制。旨在为治疗或缓解PM10/PM2.5诱发呼吸系统疾病提供新的理论和实验依据。

大量研究表明，PM2.5对机体的危害十分严重，但机制尚不清楚。本研究发现：在小鼠PM2.5急性暴露引发的肺部损伤模型中，巨噬细胞的作用十分显著，可能是此模型中联系氧化应激，炎症反应和Th应答的关键，巨噬细胞的调节作用可能通过NOX2和Th17相关的分子通路实现；在阿兹海默小鼠模型中我们发现，PM2.5暴露促进阿兹海默的发生和发展，PM2.5暴露后，脑内小胶质细胞被激活并呈现M1型高表达状态，小胶质细胞可能通过表达一系列炎症因子和直接接触等方式在神经元损伤、阿兹海默发生发展中发挥重要作用；氧化应激反应在PM2.5所致肺部急性损伤中作用显著，PM2.5可通过诱导氧化应激反应进而活化TRPM2-Ca2+通路激活NLRP3引发小鼠肺部损伤。根据前述研究结果，我们选取了具有抗炎症抗氧化效果的复方精油，进行PM2.5所致机体危害的防治研究。结果发现复方精油熏蒸，减轻了PM2.5急性暴露所致小鼠肺部损伤，此模型中复方精油主要通过其抗氧化功能及调控Th免疫应答发挥效用；复方精油熏蒸对PM2.5急性暴露所致小鼠心脏损伤也有很好的防治效果，复方精油熏蒸可明显改善PM2.5所致小鼠心肌细胞内钙离子稳态失衡和钙通道蛋白的激活，这一功效主要通过其抗氧化作用发挥。项目详细探讨了PM2.5暴露所致机体多器官损伤的机制并在此基础上探讨了可能的防治措施，对今后这一领域的进一步深入研究起着重要作用。