胎盘间充质干细胞对尘肺小鼠模型肺脏纤维化的作用与机制研究

Pneumoconiosis is a pulmonary fibrosis caused by dust deposition in the lungs. Ningxia is an important industry basis of coal and constructive materials in China. The incidence of pneumoconiosis caused by dust is the main occupational disease that is as high as by 90.5% in this region, among them 58.9% are silicosis. Silicosis has caused a significantly negative impact on the quality of life and even the live of workers, which is the reason of causing and returning the poor for families with silicosis patients in Ningxia Hui Autonomous region. Therefore there is a scientific and actual significance in discovering novel therapeutic strategies for silicosis. Mesenchymal stem cells have been demonstrated to poss an encouraging therapeutic efficacy in pulmonary fibrosis. Our previous study also showed that placental mesenchymal stem cells were able to allieviate the pulmonary fibrosis induced by Bleomycin in mouse. Therefore, this proposal aims to investigate the function and mechanism of placental mesenchymal stem cells in the pathogenesis of pulmonary fibrosis in silicon dioxide-induced mouse silicosis on the basis of t establishment of in vitro co-culture models of epithelial cells, macrophages and/or placental mesenchymal stem cells, and a silicon dioxide-induced mouse silicosis model. In this context, the impact of silica on characteristics of epithelial mesenchymal transition, function and mechanism of placental mesenchymal stem cells in injury-repair of epithelial cells and the pathogenesis of pulmonary fibrosis in silicosis mice will be investigated. An accomplishment of this project will provide an evidence of therapeutic effect of mesenchymal stem cells in silicosis, and experimental methods for stem cell therapy in pneumoconiosis.

尘肺是由粉尘在肺脏内沉积导致的肺脏纤维化。宁夏地区尘肺发病率占职业病的90.5%，其中矽肺占58.9%， 严重影响劳动者生活质量和生命，是该地区许多家庭致贫和返贫的主要原因。因此寻求新的治疗手段对宁夏地区劳动者的健康和家庭有着重大的科学和社会意义。间充质干细胞在肺脏纤维化的治疗中取得令人鼓舞的结果，但其作用机制远未被阐明。我们前期研究表明胎盘来源的间充质干细胞能够显著减轻博来霉素诱导的小鼠肺脏纤维化。因此本项目以期通过建立肺脏上皮细胞与巨噬细胞共培养模型、肺脏上皮细胞、巨噬细胞与胎盘间充质干细胞共培养模型及二氧化硅诱导小鼠矽肺模型的基础上，探究二氧化硅对人肺脏上皮细胞间质化特征的作用机制、胎盘间充质干细胞对肺脏上皮细胞的损伤保护作用以及对二氧化硅诱导小鼠矽肺纤维化调节作用及机制，从而揭示胎盘间充质干细胞对二氧化硅诱导矽肺的修复作用与机制，从而为临床干细胞治疗矽肺研究提供理论依据和实验方法。

矽肺是一种由吸入硅尘引起的职业病，其特征是进行性肺纤维化，预后不良。二氧化硅重复暴露于二氧化硅诱导气道上皮细胞损伤，导致上皮干细胞的增殖衰竭，最终导致肺重塑和矽肺的发展。因此明确发病机制并寻求新的治疗手段对劳动者的健康和家庭有着重大的科学和社会意义。本项目通过二氧化硅对人肺脏上皮细胞间质化特征的作用机制、二氧化硅诱导小鼠矽肺纤维化调节作用及机制、以及上皮细胞损伤修复的作用机制研究，证实了Wnt/β-catenin和NOX4信号通路之间存在一个正反馈循环，可能促进了硅尘暴露下肺上皮细胞的上皮-间质转化(EMT)，为研究Wnt/β-catenin和NOX4信号互作在肺上皮细胞损伤和矽肺发病机制中的促纤维化作用提供了新的研究思路；揭示了Wnt/β-catenin信号通路在矽肺发病机制中的潜在作用，并证明通过Dkk1基因转导靶向Wnt/β-catenin信号通路可能是防治矽肺病的一种途径；明确了Bmi1是在矽肺病发展过程中参与维持肺上皮干细胞自我更新、增殖和分化的关键转录因子。从而揭示二氧化硅诱导矽肺的作用与机制，为临床干细胞治疗矽肺研究提供理论依据。