E3泛素连接酶LMO7促进巨噬细胞焦亡增强特发性肺纤维化的机制研究及药物靶标鉴定

特发性肺纤维化（IPF）是一种因肺部异常的炎症损伤修复而导致进行性肺间质纤维化的难治性疾病，阐明其病理机制和发现有效药物靶标是亟待解决的科学问题。肺巨噬细胞通过焦亡参与调控IPF的炎症反应及纤维化损伤，但调控机制尚不清楚。基于前期发现E3泛素连接酶LMO7在IPF病人的肺巨噬细胞高表达，巨噬细胞特异性Lmo7敲除小鼠肺纤维化明显减弱，且Lmo7缺失的巨噬细胞焦亡明显减弱，本研究拟阐明LMO7通过巨噬细胞介导IPF的损伤机制；揭示LMO7促进巨噬细胞焦亡增强IPF的分子机制；解析LMO7泛素化GSDMD促进细胞焦亡的分子细节；评价已筛选“老药”二苯美仑阻断LMO7与GSDMD结合，缓解IPF的药理机制。最终阐明LMO7通过泛素化GSDMD，增强巨噬细胞焦亡，介导IL-1β、IL-18和HMGB1释放，导致肺部炎症损伤和纤维化形成的分子病理机制，为治疗IPF提供新型药物作用靶标和潜在药物。

Idiopathic pulmonary fibrosis (IPF) is a severe and fatal disease caused by abnormal inflammatory progresses of pulmonary injury and repair. It is of importance to unveil the molecular and pathological mechanisms and find potential drug targets for treating IPF. Macrophages play a vital role in the inflammatory injury and fibrosis pathogenesis of idiopathic pulmonary fibrosis via pyroptosis, however the regulatory mechanism remains largely unknown. Here, we found that LIM domain only protein 7 (LMO7), an E3 ubiquitin ligase, was highly expressed on alveolar macrophages of IPF patients. Then, we created a macrophage specific Lmo7 deficient mice (LysM-Cre Lmo7fl/fl) and found that pulmonary fibrosis was attenuated in LysM-Cre Lmo7fl/fl mice in response to bleomycin challenge. In addition, the pyroptosis was also reduced in Lmo7 deficient macrophages. Based on these supporting data, we will comprehensively investigate this project by following 4 specific aims: (1) To determine how LMO7 modulates IPF via regulation of macrophage activation; (2) To determine how LMO7 modulates macrophage pyroptosis and the role of pyroptosis in IPF; (3) To determine how LMO7 regulates GSDMD ubiquitin and its role in IPF; (4) To determine how bifemelane, an 'old medicine', blocks the interaction of LMO7 and GSDMD and whether bifemelane alleviates bleomycin-induced pulmonary fibrosis. Collectively, our studies will unveil that LMO7 is required for macrophage pyroptosis via inducing GSDMD ubiquitin, which in turn leads to release of IL-1β, IL-18 and HMGB1 and promotes the pulmonary fibrosis. Our findings will not only identify LMO7 as a new potential drug target, but also provide bifemelane as a promising drug for treating IPF.