Wan Hui-Qi, Xie Ling-Feng, Li Hong-Lin, Ma Yan, Li Qiu-Hui, Dai Meng-Qing, Fu Yuan-Dong, Li Wen-Jun, Zhou Jin-Pei, Qian Min-Yi, Shen Xu
Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
Acta Pharmacol Sin. 2025 May 14. doi: 10.1038/s41401-025-01558-y.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by complex aetiologies involving the accumulation of inflammatory cells, such as macrophages, in the alveoli. This process is driven by uncontrolled extracellular matrix (ECM) deposition and the development of fibrous connective tissues. Here, we observed that the mRNA expression of Ffar1, the gene encoding G protein-coupled receptor 40 (GPR40), is repressed, while Cd36 is increased in the bronchoalveolar lavage fluid (BALF), which is predominantly composed of alveolar macrophages, of IPF patients. Furthermore, the GPR40 protein was found to be largely adhered to macrophages and was pathologically downregulated in the lungs of bleomycin (BLM)-induced PF model mice (PF mice) compared with those of control mice. Specific knockdown of GPR40 in pulmonary macrophages by adeno-associated virus 9-F4/80-shGPR40 (AAV9-shGPR40) exacerbated the fibrotic phenotype in the PF mice, and activation of GPR40 by its determined agonist compound SC (1,3-dihydroxy-8-methoxy-9H-xanthen-9-one) effectively protected the PF mice from pathological exacerbation. Moreover, Ffar1 or Cd36 gene knockout mouse-based assays were performed to explore the mechanism underlying the regulation of GPR40 activation in pulmonary macrophages with compound SC as a probe. We found that compound SC mitigated pulmonary fibrosis progression by preventing M2 macrophage polarization from exerting profibrotic effects through the GPR40/PKD1/CD36 axis. Our results strongly support the therapeutic potential of targeting intrinsic GPR40 activation in pulmonary macrophages for IPF and highlight the potential of compound SC in treating this disease.
特发性肺纤维化（IPF）是一种慢性进行性间质性肺疾病，其病因复杂，涉及肺泡中炎性细胞（如巨噬细胞）的积聚。这一过程由不受控制的细胞外基质（ECM）沉积和纤维结缔组织的形成驱动。在此，我们观察到，在IPF患者主要由肺泡巨噬细胞组成的支气管肺泡灌洗液（BALF）中，编码G蛋白偶联受体40（GPR40）的基因Ffar1的mRNA表达受到抑制，而Cd36表达增加。此外，发现GPR40蛋白大量附着于巨噬细胞，与对照小鼠相比，在博来霉素（BLM）诱导的肺纤维化模型小鼠（PF小鼠）的肺中，GPR40蛋白在病理上表达下调。通过腺相关病毒9-F4/80-shGPR40（AAV9-shGPR40）特异性敲低肺巨噬细胞中的GPR40会加剧PF小鼠的纤维化表型，而其特定激动剂化合物SC（1,3-二羟基-8-甲氧基-9H-呫吨-9-酮）激活GPR40可有效保护PF小鼠免受病理恶化。此外，以Ffar1或Cd36基因敲除小鼠为基础进行实验，以化合物SC作为探针探索肺巨噬细胞中GPR40激活调控的潜在机制。我们发现，化合物SC通过阻止M2巨噬细胞极化，使其无法通过GPR40/PKD1/CD36轴发挥促纤维化作用，从而减轻肺纤维化进展。我们的结果有力地支持了靶向肺巨噬细胞中内源性GPR40激活对IPF的治疗潜力，并突出了化合物SC治疗该疾病的潜力。
