辐射诱导肺泡上皮间质转化在放射性肺纤维化中的作用及Treg的调节机制研究

Radiation-induced pulmonary fibrosis is one of clinically difficult problem in radiation therapy to the chest, and become the focus in radiation medical research. In the development of pulmonary fibrosis, the key cells, fibroblasts, derive from different sources. Up to 30% of fibroblasts may be from epithelial-mesenchymal transition. Our team recently found that irradiation on the mice's thorax induced alveolar epithelial-mesenchymal transition. As a major role in immune balance, regulatory T cells (Tregs) also were damaged by irradiation in this animal model. After intervening in this injury of Treg, the incidence rate of alveolar epithelial-mesenchymal transition decreased, while development of radiation-induced pulmonary fibrosis was retarded. Together we suppose that radiation is able to induce alveolar epithelial-mesenchymal transition, and Tregs regulate this procedure, which involved in radiation-induced pulmonary fibrosis. In this project we plan to study the specific mechanism of radiation-induced epithelial-mesenchymal transition, focus on the regulating function of Tregs to radiation-induced epithelial-mesenchymal transition, in order to provide novel idea for demonstrating pathogenesis and therapeutic measure in radiation-induced pulmonary fibrosis.

放疗过程中放射性肺纤维化的发生严重阻碍了其临床应用，如何防治已成为临床及基础研究的热点。肺纤维化发病过程中，关键效应细胞（成纤维细胞）的来源具有异质性，其中肺泡上皮间质转化而来的细胞占较大比例。本课题组前期研究发现，辐射诱导肺纤维化过程中存在肺泡上皮间质转化，而重要的免疫调节细胞调节性T淋巴细胞（Treg）的辐射损伤与肺泡上皮间质转化存在密切联系，干预Treg的损伤可抑制肺泡上皮间质转化，同时放射性肺纤维化进程减缓。由此我们提出Treg调节辐射诱导肺泡上皮间质转化参与放射性肺纤维化的发生的假设。本项目拟对Treg调节辐射诱导肺泡上皮间质转化作用进行研究，着重探讨Treg调节辐射诱导肺泡上皮细胞转化的作用机制及其中的辐射特征性信号转导通路，以期为阐明放射性肺纤维化的发病机制和防治研究提供新思路。

放疗过程中放射性肺纤维化的发生严重阻碍了其临床应用。肺纤维化发病过程中，关键效应细胞（成纤维细胞）的来源具有异质性，其中肺泡上皮间质转化而来的细胞占较大比例。本课题组研究发现，辐射诱导肺纤维化过程中存在肺泡上皮间质转化，而重要的免疫调节细胞调节性T淋巴细胞（Treg）的辐射损伤与肺泡上皮间质转化存在密切联系，干预Treg的损伤可抑制肺泡上皮转化，同时放射性肺纤维化进程减缓，而β-连环蛋白通路介导该作用。进一步的研究发现辐射可诱导人支气管上皮细胞发生自噬反应，其介导辐射诱导肺泡上皮间质转化，而 miRNA Let-7i在辐射诱导肺上皮间质转化中也起重要作用。采用TGF-β3可通过抑制上皮间质转化抑制小鼠放射性肺纤维化。本项目着重探讨了Treg调节辐射诱导肺泡上皮细胞转化作用，着重探讨Treg调节辐射诱导肺泡上皮细胞转化的作用机制及其中的辐射特征性信号转导通路，为阐明放射性肺纤维化的发病机制和防治研究提供新思路。