Wang Lei, Lv Weichao, Mao Hongcai, Chen Qi, Ma Yuntian, Zhang Luoqian, Ruan Yang, Zhang Chaofeng
Sino-Jan Joint Lab of Natural Health Products Research, School of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, 210009, China.
Department of Thoratic Surgery, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210000, Jiangsu, China.
Free Radic Biol Med. 2025 Sep;237:251-269. doi: 10.1016/j.freeradbiomed.2025.05.435. Epub 2025 Jun 3.
Phospholipase A2 Group IIA (PLA2G2A), a secretory member of the phospholipase family, plays key roles in various physiological processes across multiple metabolic tissues. While PLA2G2A is expressed in lung epithelial cells and fibroblasts, its functions in lung injury and fibrosis remain poorly understood. In this study, we characterized the critical role of PLA2G2A in pulmonary fibrosis (PF) in both human patients and bleomycin (BLM)-induced PF mouse models. We found that PLA2G2A is significantly upregulated in the fibrotic lungs of both PF patients and mice, with its expression positively correlating with fibrotic gene markers. Functionally, PLA2G2A induced pyroptosis in lung epithelial cells, leading to mitochondrial damage, activation of the STING-NLRP3-GSDMD axis, and increased expression of α-SMA and COL1A1 in fibroblasts. Additionally, recombinant PLA2G2A protein directly induced the expression of IDO1 and α-SMA in human lung fibroblasts (HLFs) and primary mouse lung fibroblasts (MLFs). Mechanistically, PLA2G2A appears to alter lipid metabolism either directly or by activating IDO1, which exacerbates PF through AHRR-mediated inhibition of AHR. For therapeutic strategy, we administered Varespladib (a PLA2G2A inhibitor) and Indoximod (the selective IDO1 inhibitor) to the animals, both of which were found to mediate the progression of PF. Our findings suggest that PLA2G2A plays a central role in pro-fibrotic processes by modulating epithelial cells and fibroblasts, thereby promoting extracellular matrix production. Given its involvement in PF pathogenesis, PLA2G2A may serve as a potential therapeutic target for PF, with PLA2G2A inhibitors offering a promising strategy for clinical treatment.
磷脂酶A2第二亚家族A组（PLA2G2A）是磷脂酶家族的一种分泌型成员，在多种代谢组织的各种生理过程中发挥关键作用。虽然PLA2G2A在肺上皮细胞和成纤维细胞中表达，但其在肺损伤和纤维化中的功能仍知之甚少。在本研究中，我们在人类患者和博来霉素（BLM）诱导的肺纤维化小鼠模型中，明确了PLA2G2A在肺纤维化（PF）中的关键作用。我们发现，PLA2G2A在PF患者和小鼠的纤维化肺组织中显著上调，其表达与纤维化基因标志物呈正相关。在功能上，PLA2G2A诱导肺上皮细胞发生焦亡，导致线粒体损伤、STING-NLRP3-GSDMD轴激活，以及成纤维细胞中α-SMA和COL1A1表达增加。此外，重组PLA2G2A蛋白直接诱导人肺成纤维细胞（HLF）和原代小鼠肺成纤维细胞（MLF）中IDO1和α-SMA的表达。从机制上讲，PLA2G2A似乎直接或通过激活IDO1来改变脂质代谢，而IDO1通过AHRR介导的AHR抑制加重PF。在治疗策略方面，我们给动物施用了伐瑞普拉德（一种PLA2G2A抑制剂）和吲哚莫德（选择性IDO1抑制剂），发现二者均可介导PF进展。我们的研究结果表明，PLA2G2A通过调节上皮细胞和成纤维细胞在促纤维化过程中发挥核心作用，从而促进细胞外基质产生。鉴于其参与PF发病机制，PLA2G2A可能成为PF的潜在治疗靶点，PLA2G2A抑制剂为临床治疗提供了一种有前景的策略。
