Lipoxin A4 Regulates M2 Macrophage-Derived Exosomal miR-25-5p to Protect Cell Pyroptosis in Bronchopulmonary...

Bronchopulmonary dysplasia (BPD) involves macrophage-driven immunoinflammation, while macrophage-derived exosomes act as key extracellular vehicles linking macrophage-driven inflammation with tissue injury. Emerging evidence suggests that Lipoxin A4 (LXA4) modulates macrophage immune responses. However, the precise role of LXA4 in regulating macrophage function in BPD and its underlying mechanisms remains unclear. Neonatal rats were exposed to 85% hyperoxia to establish a BPD model. LXA4 or M2-polarized macrophage-derived exosomes (M2-exo) were injected intraperitoneally, and pulmonary inflammation, macrophage polarization and pyroptosis were examined. M2-exo were co-cultured with type II alveolar epithelial cells (AT2) to further validate the animal experimental findings and explore underlying mechanisms. Here, we find that monocyte-derived macrophages were activated in BPD. LXA4 significantly ameliorated lung tissue injury and pyroptosis by promoting M2-exos release. Single-cell transcriptomic profiling revealed altered macrophage-epithelial cell interactions in BPD lungs. Mechanistic studies demonstrated that M2-exo-derived miR-25-5p alleviated AT2 pyroptosis, which targeted nuclear receptor binding protein 2 (NRBP2) and downregulated the PI3K/AKT pathway. Additionally, PI3K inhibition (LY294002) or miR-25-5p knockdown reversed these protective effects. This study proved that LXA4 promotes M2 macrophage polarization and enhances exosomal miR-25-5p release, thereby inhibiting pyroptosis via the NRBP2/PI3K/AKT axis and ameliorating BPD lung injury. These findings elucidate the lung-protective mechanism of LXA4 and highlight a novel macrophage-AT2 cross-talk in BPD, providing new therapeutic strategies for BPD-related lung injury.