矽肺患者约占我国尘肺总病例的50%，是尘肺中危害最严重的一种职业病。矽肺的病理过程主要表现为肺部炎症纤维化。前期研究发现矽肺小鼠淋巴细胞活化诱导受体4-1BB的水平显著高于对照组。4-1BB是T细胞活化共刺激分子，参与调控多种疾病。目前对矽肺免疫调控机制尚未十分清楚，特别是4-1BB调控矽肺炎症纤维化的研究尚未见报道。本研究拟通过基因敲除及激活抗体干预等方法，利用矽肺动物模型，研究4-1BB信号通路调控矽肺炎症纤维化的作用及分子机制；利用4-1BB基因敲除鼠原代细胞，研究SiO2激活4-1BB信号通路及对T细胞分化的调控机制；利用矽肺患者临床样本，研究4-1BB信号通路对矽肺患者纤维化的调控作用及其机制。以探明矽肺中4-1BB信号通路激活及其调控矽肺炎症纤维化的分子机制。本项目有望为延缓和阻抑矽肺炎症纤维化发生发展提供潜在的免疫分子靶标。

Silicosis is the most severe and harmful occupational disease, which composed 50 percent of the pneumoconiosis. The pathological change of the silicosis is lung inflammation and fibrosis. Our previous data showed that the level of receptor induced by lymphocyte activation 4-1BB in silicosis mice was significant higher than that in control mice. As the co-stimulation factor of T cell activation, 4-1BB takes part in the immune regulation of many diseases. However, the immunological mechanism during the pathology process of silicosis is not clearly demonstrated yet. What’s more, the regulatory mechanism of 4-1BB during the immune response in silicosis chronic inflammation and fibrosis is investigated rarely. Firstly, our study tries to analyze the molecular regulatory mechanism of 4-1BB signal pathway on silica induced lung inflammation and fibrosis in silicosis animal model by using gene knockout mice and agonistic antibody. Secondly, our study tries to research the molecular mechanism of 4-1BB signal pathway activation and the regulation of T cell’s differentiation by using the primary cells culture of 4-1BB knockout mice in vitro. Finally, our study try to investigated the regulatory role and molecular mechanism of 4-1BB on silicosis patients’ fibrosis by testing the activation of 4-1BB and its related signal pathways. The aim of our study is to illustrate molecular mechanism of the activation of 4-1BB signal pathways and the regulation of 4-1BB pathway on silicosis lung fibrosis. It is believed that if we demonstrated the mechanism of 4-1BB activation and/or the immune regulation of 4-1BB on silicosis development successfully, the potential molecular targets will be provided to help delaying the development of silicosis and curing the lung fibrosis.