薯蓣皂苷调控巨噬细胞自噬阻抑矽肺纤维化发生发展的作用机制

Silicosis is one kind of pneumoconiosis induced by inhalation of silica dust during occupational environment, which is characterized by the chronic lung inflammation and lung fibrosis. Silicosis patients consists 50 percent of the pneumoconiosis, which is the most sever and harmful occupational disease. However, the pathogenesis and the immunological modulation of silicosis are not clear yet. Our previous researches have demonstrated that the abnormal autophagy activities of alveolar macrophages in silicosis patients’ bronchoalveolar lavage fluid played a key role during the development of silicosis. And dioscin could postpone the fibrotic process by regulating autophagy. On the basis of previous work, our project will take advantage of multiple methods, such as immunology, molecular, cellular and animal model. The objective of our project is to define the mechanism of autophagy inhibition on the clearance of mitochondria and the secretion of proinflammatory cytokines; to study the role of dioscin on promoting the autophagy activity in macrophages; to demonstrate that the regulatory role and its deep mechanism of dioscin on postpone the fibrotic process by regulating autophagy. Hopefully, the novel experimental and theoretical foundation could be provided to help postponing and inhibiting the silicosis development.

矽肺是由于在生产过程中吸入大量矽尘而导致的以肺部慢性炎症和肺组织纤维化为主要病理改变的尘肺病。矽肺患者约占我国尘肺总病例的50%，是危害最严重的一种职业病。但目前矽肺的发病及免疫调控机制尚不明确。我们前期研究发现，矽肺患者肺泡巨噬细胞自噬活动的异常可能在矽肺发生发展中具有关键作用，而薯蓣皂苷可能通过调控自噬在矽肺发生发展中发挥保护作用，但其具体分子机制尚不清楚。本项目在前期工作基础上，拟综合运用免疫、分子、细胞和动物模型等多种研究手段，明确自噬功能抑制对矽尘所致受损线粒体清除和促炎因子分泌的作用机制；研究薯蓣皂苷促进巨噬细胞自噬的作用机制；研究薯蓣皂苷调控自噬对延缓矽肺纤维化的作用及其机制，旨在为延缓和阻抑矽肺纤维化提供新的实验和理论依据。

矽肺是由于生产过程中长期吸入游离二氧化硅含量较高的粉尘而引起的以肺组织纤维化为主的职业性疾病，是最主要的尘肺病类型。虽然我国在控制粉尘的产生和扩散、降低作业场所粉尘浓度、改善劳动环境方面做了大量工作，而且已取得了一定成绩，但粉尘危害的形式依然严峻。矽肺所导致的肺组织纤维化的病理改变是不可逆的，但矽肺发病一般呈缓慢，进行性的病理过程。因此，探索肺纤维化发病的免疫分子机制以延缓或阻断纤维化发生发展进程的策略，仍具有重要的实际意义。.肺泡巨噬细胞是矽尘的最主要靶细胞和促进纤维化进展的重要免疫细胞，研究表明矽肺患者肺泡巨噬细胞自噬活动的异常可能在矽肺发展中具有关键作用。本项目以中药单体薯蓣皂苷调控巨噬细胞自噬为切入点，以小鼠肺泡巨噬细胞系及实验性矽肺模型小鼠为研究对象，明确薯蓣皂苷可通过调控巨噬细胞自噬阻抑矽肺纤维化进展。研究表明，薯蓣皂苷通过促进肺泡巨噬细胞自噬，增强对矽尘损伤线粒体的清除、减轻线粒体介导凋亡通路的激活。薯蓣皂苷使肺泡巨噬细胞抵抗矽尘所致的凋亡，减少细胞内过量的线粒体ROS产生。抑制巨噬细胞分泌促炎促纤维化因子，缓解矽尘所致的肺部炎症和纤维化。除此之外，课题组研究发现矽肺纤维化进展中存在内质网应激现象，其与细胞自噬密切相关。研究发现IRE1α-TXNDC5信号通过调控纤维母细胞内质网应激影响细胞活化，体内抑制IRE1α功能，可以有效减轻由矽尘引起的肺纤维化。.综合以上研究结果，本项目研究成果揭示了调控矽肺纤维化发展的新的分子机制，并为延缓纤维化进展提供了新的潜在分子靶点和治疗策略。.