Kwak Doyun, Ling Song, Subbotina Natalya, Shayman James A, Sisson Tomas H, Kim Kevin K
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States.
Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States.
Am J Physiol Lung Cell Mol Physiol. 2025 Aug 1;329(2):L214-L223. doi: 10.1152/ajplung.00038.2025. Epub 2025 Jun 26.
Recent evidence suggests that oxidized phospholipids (oxPLs) play a critical role in the pathogenesis of pulmonary fibrosis. The precise mechanism by which oxPL contributes to fibrosis remains unknown and likely involves complex interactions between epithelial cell injury, phospholipid accumulation, and macrophage activation. We have previously identified lysosomal phospholipase A2 (LPLA2, PLAG15) as a critical enzyme involved in the catabolism of oxPL, especially within alveolar macrophages. We hypothesized that LPLA2 activity would mitigate the accumulation of oxPL within macrophages and thereby influence the development of pulmonary fibrosis. Using wild-type (WT) and LPLA2-null mice, we induced lung injury with bleomycin and assessed lung fibrosis severity, bronchoalveolar lavage (BAL) cell lipid accumulation, and monocyte/macrophage profibrotic activation. Our results show that LPLA2-null mice accumulated significantly more intracellular lipid within their alveolar cells, exhibited higher transforming growth factor-β (TGFβ) levels in their BAL fluid, and developed more severe fibrosis after bleomycin injury compared with WT mice. In vitro studies confirmed that LPLA2 expression in WT bone marrow-derived macrophages limits oxPL accumulation and thereby mitigates their profibrotic activation. Overexpression of LPLA2 in WT mice reduced alveolar cell lipid accumulation, decreased BAL fluid (BALF) TGFβ levels, and attenuated fibrosis. These findings underscore the critical role that LPLA2 plays in regulating lipid accumulation and suggest that enhancing LPLA2 activity within alveolar cells (or the alveolar compartment) could attenuate the fibrotic response following lung injury. By identifying LPLA2 as a key regulator in this pathway, we propose that targeting LPLA2 and related lipid metabolic processes offers a promising therapeutic strategy. During lung injury and fibrosis, there is accumulation of oxidized phospholipid within macrophages in the alveolar space. This promotes profibrotic macrophage activation, resulting in pulmonary fibrosis. We find that degradation of oxidized phospholipid by lysosomal phospholipase A2 is important in preventing fibrosis. This offers a potential therapeutic target.
近期证据表明，氧化磷脂（oxPLs）在肺纤维化的发病机制中起关键作用。oxPL促成纤维化的确切机制尚不清楚，可能涉及上皮细胞损伤、磷脂积累和巨噬细胞激活之间的复杂相互作用。我们之前已确定溶酶体磷脂酶A2（LPLA2，PLAG15）是参与oxPL分解代谢的关键酶，尤其是在肺泡巨噬细胞内。我们推测LPLA2活性会减轻巨噬细胞内oxPL的积累，从而影响肺纤维化的发展。利用野生型（WT）和LPLA2基因敲除小鼠，我们用博来霉素诱导肺损伤，并评估肺纤维化严重程度、支气管肺泡灌洗（BAL）细胞脂质积累以及单核细胞/巨噬细胞促纤维化激活情况。我们的结果显示，与WT小鼠相比，LPLA2基因敲除小鼠的肺泡细胞内积累了显著更多的细胞内脂质，其BAL液中转化生长因子-β（TGFβ）水平更高，且在博来霉素损伤后发生了更严重的纤维化。体外研究证实，WT骨髓来源巨噬细胞中LPLA2的表达限制了oxPL的积累，从而减轻了它们的促纤维化激活。WT小鼠中LPLA2的过表达减少了肺泡细胞脂质积累，降低了BAL液（BALF）TGFβ水平，并减轻了纤维化。这些发现强调了LPLA2在调节脂质积累中所起的关键作用，并表明增强肺泡细胞（或肺泡腔）内的LPLA2活性可减轻肺损伤后的纤维化反应。通过确定LPLA2是该途径中的关键调节因子，我们提出靶向LPLA2及相关脂质代谢过程提供了一种有前景的治疗策略。在肺损伤和纤维化过程中，肺泡空间内的巨噬细胞中会积累氧化磷脂。这促进了促纤维化巨噬细胞激活，导致肺纤维化。我们发现溶酶体磷脂酶A2对氧化磷脂的降解在预防纤维化中很重要。这提供了一个潜在的治疗靶点。
