芸香科生物碱通过干预COX2/PGE2介导的EMT预防ARDS相关肺纤维化的机制研究

肺上皮细胞广泛受损及过度修复，是急性呼吸窘迫综合症（ARDS）相关肺纤维化的特点，也是高死亡率的原因之一。上皮-间质转化（EMT）是肺纤维化的重要环节。研究提示芸香科生物碱具有抗肺纤维化作用，增加肺上皮细胞E-cadherin，减少SMA，且上调COX2/PGE2，提示可能与调控COX2/PGE2介导的EMT相关。为此，本研究创新性提出调控肺上皮细胞EMT可能是芸香科生物碱抗纤维化的机制。因此，本项目以ARDS相关肺纤维化体内外模型，研究芸香科生物碱抗纤维化作用与抑制EMT的关系；然后采用基因转染、基因敲除、分子生物学等技术，研究芸香科生物碱对肺上皮细胞EMT、COX2/PGE2以及可能下游信号通路分子的影响，进一步阐明其通过干预COX2/PGE2介导的EMT预防ARDS相关肺纤维化的机制。本研究为芸香科生物碱的抗纤维化提供新的理论依据，并为ARDS相关肺纤维化寻找可能的预防药物。

Acute respiratory distress syndrome (ARDS) associated pulmonary fibrosis is a high mortality disease characterized by diffuse damage of lung epithelial cells and excessive repair. Epithelia-mesenchymal transition (EMT) is an essential part of pulmonary fibrosis. Previous studies showed that the rutaceae alkaloids potently inhibited pulmonary fibrosis, and unregulated the levels of E-cadherin, COX2/PGE2, and reduced the levels of SMA. These results suggested that the anti-fibrotic effect of the alkaloids might be correlated with COX2/PGE2-mediated EMT. Therefore, we creatively suggest that rutaceae alkaloids might inhibit EMT that would be the new mechanism of anti-pulmonary fibrosis. The current project focuses on clarifying the correlation between the antifibrotic effects and EMT of lung epithelial cells of rutaceae alkaloids using ARDS-associated pulmonary fibrosis model. Then, using the techniques of gene transfection, gene knockout, and molecular biology, the project aims at investigation on the effects of the alkaloids on EMT of epithelial cells, COX2/PGE2 and downstream signaling molecules. Furthermore, the project takes aim at clarifying the mechanism of the alkaloids on regulation of epithelial EMT via COX2/PGE2 signal pathways. The project may elucidate the anti-ARDS associated pulmonary fibrosis effect and mechanism of the rutaceae alkaloids from a novel perspective, and provide a new insight on developing antifibrotic agent for clinical application.