Degradation of oxidized phospholipids by lysosomal phospholipase A2 regulates pulmonary fibrosis.

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.