PI3K介导的细胞自噬在矽肺纤维化中的作用研究

我国是粉尘危害最严重的国家之一，尘肺至今还没有特效治疗方法，主要是因为其发病机制尚不清楚。矽肺是尘肺中危害最严重的一种，研究表明，肺泡巨噬细胞是粉尘作用的主要靶细胞，然而，细胞凋亡学说并不能充分说明矽肺纤维化的发病机制。自噬是细胞的一种防御性或生存机制，改变自噬过程或自噬的缺陷可能会导致疾病的发生。但还没有直接的证据说明自噬与矽肺纤维化之间的联系。本项研究采用人群研究和动物实验相结合的方法探讨自噬在矽肺发生发展过程中的作用，对接尘观察对象、不同期别矽肺患者肺灌洗回收液中巨噬细胞以及矽肺模型大鼠染尘后不同纤维化程度肺组织和肺泡巨噬细胞进行自噬的检测，并检测分析Ⅰ型PI3K介导的Akt-mTOR、Ⅲ型PI3K介导的Beclin1和 ROS-mTOR信号通路关键分子的mRNA和蛋白表达水平，探讨矽尘刺激时自噬发生的主要分子机制。本研究以新的视角探讨矽肺发病机制，将为矽肺早期干预提供理论依据。

China is one of the most serious countries in dust hazard. Pneumoconiosis still does not have special treatment mainly because of its pathogenesis still not clear. Silicosis is one of the most harmful pneumoconiosis. Researches indicated that alveolar macrophages (AMs) are the main target cells in dust effects. However, the cell apoptosis theory can't fully explain the pathogenesis of silicosis. Autophagy is a defensive or cell survival mechanism. Changing autophagy process or autophagy defects may cause diseases. But there is no direct evidence proving the relationship between autophagy and silicosis. This study used both of population study and animal experiments to discuss the functions of autophagy in the occurrence and development of silicosis. Autophagy, the expression of mRNA and protein level of PDK1, Akt and mTOR mediated by PI3K-Ⅰ, Beclin1 mediated by PI3K-Ⅲ of AMs from lung lavage recovery liquid of silicosis observers and patients at stageⅠ,Ⅱand Ⅲ will be determined. Also, autophagy, the expression of mRNA and protein level of PDK1, Akt, mTOR, Beclin1, PI3K of AMs and lung tissue from silicotic model rats in different fibrosis stages after instilling silica do. The present study purposes to describe the pathogenesis of silicosis with new point of view which will provide theoretical basis for silicosis intervention in early period.