Granulins调控尘肺炎性反应与纤维化的作用机制研究

pneumoconiosis is a fibrotic lung disease caused by inhalation of dust, and there is no effective treatment that could efficiently control the onset and progression of pneumoconiosis. Antibody-targeted therapy is a novel precision treatment strategy, which has been recognized for its high efficiency and low side effects in clinical practice. In our preliminary study, we obtained a neutralizing mouse monoclonal anti-Grn antibody(PGN-H8). We found that PGN-H8 has a good anti-pulmonary fibrosis effect in the mouse silicosis model. GRN gene regulates the body's innate immunity and post-injury repair, which are closely related to fibrosis. Nevertheless, the mechanism involving GRN in pulmonary fibrosis has not been reported. Our preliminary results suggest that GRN promotes both the inflammatory response of dust stimulated alveolar macrophage and the proliferation and differentiation of myofibroblast. In this study, antibody microarrays, gene sequencing, proteomics, immunohistochemistry and Co-IP were use to study the molecular mechanism of GRN in Pneumoconiosis. Our study may establish a theoretical foundation for the further study of the function and clinical application of Grn gene, and provide new concept for targeted therapy of pneumoconiosis.

尘肺病是由长期吸入致病粉尘引起的肺纤维化病，目前尚无有效治疗方法。吸入性粉尘引起的炎性反应和促纤维化因子上调是尘肺纤维化的主要病因，针对关键炎性与促纤维化因子的抗体靶向干预策略有望突破尘肺病临床防治的困境。GRN基因调节炎性，调控成纤维细胞分化与尘肺纤维化密切相关，但在尘肺纤维化中的作用机制尚不清楚。前期研究结果证明：GRN在尘肺中高表达，是尘肺发病过程中潜在的关键炎性和促纤维化生长因子；抗GRN单抗PGN-H8（前期筛选得到）在体内具有良好的干预小鼠矽肺纤维化作用。在本项目中，我们拟在前期基础上用GRN基因敲除鼠和细胞，建立体内外尘肺炎性和纤维化模型综合利用抗体芯片、基因测序、蛋白组、免疫组化和Co-IP-质谱鉴定等技术深入研究GRN调控尘肺炎性发生和纤维化进展的分子机制，为PGN-H8抗体靶向干预尘肺纤维化的临床应用提供理论依据。

尘肺病是由长期吸入致病粉尘引起的肺纤维化病，目前尚无有效治疗方法。吸入性粉尘引起的炎性反应和促纤维化因子上调是尘肺纤维化的主要病因。Grn基因调节炎性反应和成纤维细胞分化，与尘肺纤维化密切相关，但其在肺纤维化中的作用机制尚不清楚。本课题用Grn基因敲除鼠和各种肺组织细胞，建立体内外尘肺炎性和纤维化模型，并综合利用组学、分子生物学和卫生毒理学等技术方法深入研究了Grn调控尘肺炎症和纤维化进展的分子机制。课题结果揭示了Grn基因促进矽肺炎症和纤维化的作用及其对肺泡巨噬细胞炎性应答、肺成纤维细胞增殖和分化以及肺上皮细胞上皮间质转化的分子作用机制。本研究结果为尘肺病的分子诊断和治疗提供了新的思路。