PPARs辅助因子在香烟诱导的肺泡巨噬细胞极化及功能损伤中的作用及机制研究

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease characterized by progressive airflow limitation. Cigarette smoking is one of the most important risk factors of COPD and persistent airway inflammation. Eliminating the inflammation induced by cigarette smoke is a goal of COPD treatment. Peroxisome proliferator-activated receptor gamma (PPARγ) have been identified in lung tissue and in the cells associated with inflammation in the lung. Therefore, PPARγ agonists may be the next choice for COPD treatment. To investigate the effects and the mechanism of PPARγ on CS induced inflammation, we examine the expression and the activity of PPARγ induced by cigarette smoke (CS) in alveolar macrophage(AMs), and evaluate the effects of PPARγ on CS-induced defective macrophage phagocytosis. To further explore mechanism of the PPARγ on AMs function, we also study the regulation of N-CoR-PPARγ:RXR pathways, which mediated AMs polarization and activation dysfunction, by effecting on PPARγ. The study would produce a new recognization of COPD etiological factor, and provide a new target of COPD therapeutics.

慢性阻塞性肺疾病是以气流持续受限为特征的慢性炎症性疾病，长期吸烟是主要病因。本课题组前期研究中观察到过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptors，PPARγ)具有减轻烟熏所致肺气肿模型大鼠肺部炎症及肺气肿的作用，和影响模型大鼠肺泡巨噬细胞（AMs）代谢活力的作用，但其具体作用及机制尚不清楚。本课题拟在前期研究的基础上，通过体内和体外实验系统研究N-CoR-PPARγ:RXR通路对熏烟诱导巨噬细胞极化及功能损伤的影响，以深入探索PPARγ调节香烟诱导肺炎症的机制，进一步阐明慢阻肺的发病机制、寻找慢阻肺防治新药奠定基础。

慢性阻塞性肺疾病（慢阻肺）是一种以气流受限为特征的慢性气道炎症性疾病，香烟烟雾暴露是其主要病因之一，香烟通过诱导巨噬细胞损伤及功能异常参与到了慢阻肺的病理生理过程中。巨噬细胞具有异质性，可在外界环境刺激下分化为具有促炎功能的M1型和具有抗炎及免疫调理功能的M2型巨噬细胞。在慢性气道疾病患者存在巨噬细胞极化变化。此外，香烟可通过诱导气道和肺泡上皮细胞凋亡，增加气道内凋亡细胞残骸累积进而诱导肺气肿病变。既往研究中香烟对于巨噬细胞M1/M2极化以及凋亡的作用尚存有争议，且其分子机制仍有待探索。因此本研究将针对香烟对巨噬细胞M1/M2极化和凋亡的作用及其分子机制进行探索。本研究初步证实：1. CSE促进了巨噬细胞M1极化，对M2极化具有先抑制后促进的动态调节作用，AM对CSE诱导的极化改变较PM更为灵敏；2. 香烟暴露可诱导巨噬细胞M1极化激活，而PPARγ合成激动剂罗格列酮可以通过激活PPARγ/RXRα减少CSE诱导的M1极化，并促进M2极化激活；3. CSE通过激活了内质网应激和细胞内Ca2+/P38/STAT1通路，诱导了巨噬细胞系Raw264.7中caspase3依赖的凋亡，但是其凋亡过程独立于线粒体途径和ROS。