BMP-7拮抗TGF-β信号通路在石英致肺上皮-间质转化中的作用机制

Pulmonary fibrosis is the main pathological change of silicosis induced by silica dust. Pulmonary epithelial-to-mesenchymal transition(EMT) is one important source of fibroblasts in the pulmonary fibrosis. Studies have shown that BMP-7 could reverse EMT, but the mechanism is not clear. Our previous work demonstrated that TGF-β signaling pathway may be involved in EMT of type II alveolar epithelial cell treated with silica. This study on this base is to observe the change characteristics of TGF-β signal pathways(Smad and MAPK) in the EMT process through establishing EMT cell model induced by silica. The mechanisms of BMP-7 antagonizing TGF-β signal pathways(Smad and MAPK) are going to be explored through the establishment of cell models of BMP-7 gene overexpression and silence. In vivo animal studies, BMP-7 will be administered to rats with pulmonary fibrosis induced by silica to investigate the mutual relationship among EMT, pulmonary fibrosis progression and TGF-β downstream signal pathways(Smad and MAPK). This subject will confirm our hypothesis in cellular, molecular and whole levels that BMP-7 could prevent and delay pulmonary fibrosis caused by occupational exposure to silica dust through antagonizing TGF-β signal pathways(Smad and MAPK).

石英粉尘引起的肺组织纤维化是矽肺的主要病理改变，肺泡上皮细胞向间质细胞转化(EMT)是肺纤维化成纤维细胞的重要来源。已有研究表明骨形态发生蛋白-7(BMP-7)具有逆转EMT的作用，但机制不清。本课题组前期研究发现TGF-β信号通路可能参与了石英诱导的肺泡II型上皮细胞发生EMT的过程。本研究在此基础上拟通过建立石英诱导的EMT细胞模型，观察TGF-β信号通路(Smad和MAPK)在EMT中的变化特点；通过建立BMP-7基因过表达和沉默的细胞模型，探讨BMP-7拮抗TGF-β信号通路(Smad和MAPK)的作用机制；通过建立石英诱发的大鼠矽肺模型，采用BMP-7干预治疗，研究EMT、肺纤维化进展、TGF-β下游信号通路(Smad和MAPK)三者的关系。本课题拟从分子、细胞、整体水平证实我们的假说：BMP-7可能通过拮抗TGF-β信号通路（Smad和MAPK）发挥预防和延缓矽肺纤维化的作用。

石英粉尘引起的肺组织纤维化是矽肺的主要病理改变，肺泡上皮细胞向间质细胞转化(EMT)是肺纤维化成纤维细胞的重要来源。已有研究表明骨形态发生蛋白-7(BMP-7)具有逆转EMT的作用，但机制不清。本研究通过建立石英诱导的EMT细胞模型，观察TGF-β信号通路(Smad和MAPK)在EMT中的变化特点；通过建立BMP-7基因过表达和沉默的细胞模型，探讨BMP-7拮抗TGF-β信号通路(Smad和MAPK)的作用机制；通过建立石英诱发的大鼠矽肺模型，采用BMP-7干预治疗，研究EMT、肺纤维化进展、TGF-β下游信号通路(Smad和MAPK)三者的关系。研究发现：① 石英可在体外诱导上皮细胞发生EMT，Smad和p38MAPK信号通路在石英诱导的EMT中发挥重要作用；② 石英诱导的大鼠肺组织纤维化过程中存在EMT，TGF-β/Smad和p38MAPK信号通路参与这个过程。③ BMP-7可以减轻石英诱导的肺组织纤维化，BMP-7的拮抗纤维化作用与抑制EMT有关。提示BMP-7通过下调Smad及MAPK信号通路，抑制EMT发生，从而发挥预防和延缓矽肺纤维化的作用。该项研究为寻找潜在的矽肺治疗有效途径提供理论依据。