百草枯诱导Ⅱ型肺泡上皮细胞凋亡的调控机制研究

项目名称： 百草枯诱导Ⅱ型肺泡上皮细胞凋亡的调控机制研究

项目编号： No.81471851

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 董雪松

作者单位： 中国医科大学

项目金额： 56万元

中文摘要： 百草枯(PQ)是目前世界范围内广泛使用的除草剂，中毒者病死率极高。PQ所致肺间质纤维化是患者死亡的重要原因，但其发病机制尚不十分清楚。II型肺泡上皮细胞（AT II）凋亡过度被认为是纤维化早期发生中的关键事件。我们在前期工作中发现，PQ致肺损伤过程中存在ATII凋亡增多，促凋亡蛋白Bad、Bax高表达，但Fas表达增高不明显。对Caspases激活的分析也发现PQ激活了内质网应激和线粒体途径特异性的Caspases。我们推测PQ致AT II凋亡调控机制可能以内质网应激和线粒体途径为主，涉及到活性氧和细胞内钙稳态。本研究将利用细胞实验，将PQ致AT II凋亡作用机制作为研究突破点。研究结果将阐明PQ诱导AT II凋亡过程中内质网应激及线粒体凋亡通路的作用及发生机制，以及Ca2+稳态和活性氧与内质网应激和线粒体凋亡通路的关系。本研究将深化对PQ致肺损伤发病机理的认识，为有效治疗本病提供新思路。

中文关键词： 百草枯；Ⅱ型肺泡上皮细胞；凋亡；内质网应激；线粒体途径

英文摘要： Paraquat (PQ), which is a herbicide, has been widely used throughout the world. But patients with PQ poisoning were associated with high mortality. Pulmonary fibrosis caused by PQ is the important reason for patients' death, and its pathogenesis hasn't been fully understood yet. Excessive apoptosis of type II alveolar epithelial cell (AT II) is considered as the critical event during the early phase of pulmonary fibrosis. Some supporting facts were found in our prophase work. The increasing expression of the proapoptotic proteins like Bad and Bax instead of Fas were noticed in AT II isolated from the lungs of PQ-treated mice, while the analysis of the activity of Caspases also indicated that the specific Caspases from endoplasmic reticulum stress (ER stress)and mitochondrial apoptotic pathway were activated. A hypothesis is developed by our team that the ER stress and mitochondrial apoptotic pathway would be the chief pathways in the PQ-induced apoptosis of AT II involving the reactive oxygen species (ROS) and intracellular calcium homeostasis. This research, through the cellular experiments, would attach the great importance to the regulation mechanism of PQ-induced apoptosis of AT II. The results will clarify the roles of ER stress mitochondrial apoptotic pathways,the trigger factors of those pathways, and the relationship between calcium homeostasis, ROS and two apoptotic pathways. This research will enhance the comprehension of the pathogenesis and role of apoptosis of AT II during PQ-induced pulmonary injury, provide the new insight and find a new therapeutic target point for the treatment.

英文关键词： paraquat;type Ⅱ alveolar epithelial cell;apoptosis;endoplasmic reticulum stress;mitochondrial pathway