Macrophage Phenotypic Plasticity and Inflammatory Mechanisms in Hyperoxia-Induced Lung Injury

Hyperoxia-induced lung injury is a prominent inflammatory complication encountered in neonatal and adult critical care, contributing to acute lung injury and bronchopulmonary dysplasia. Although oxidative stress is a primary initiating factor, accumulating evidence suggests that dysregulated immune responses, particularly those mediated by macrophages, critically influence disease progression and resolution. Macrophages exhibit remarkable phenotypic plasticity in response to hyperoxic stress, extending beyond the conventional pro-inflammatory and anti-inflammatory polarization framework. Recent advances, including single-cell transcriptomic analyses, have revealed substantial heterogeneity among macrophage subsets, highlighting inflammatory, metabolically reprogrammed, senescent, and pyroptotic phenotypes in hyperoxic lung injury. These phenotypic shifts are tightly regulated by inflammatory signaling pathways, immunometabolic alterations, and cellular stress responses. In this review, we summarize current evidence regarding macrophage phenotypic plasticity in hyperoxia-induced lung injury, with a focus on key inflammatory pathways, metabolic reprogramming, inflammasome activation, and emerging cell fate programs such as pyroptosis and cellular senescence. We further discuss macrophage-mediated intercellular communication with epithelial and endothelial cells and its contribution to persistent inflammation and impaired lung repair. By integrating these findings, this review aims to provide updated insights into macrophage-driven inflammatory mechanisms and to highlight potential avenues for therapeutic modulation in hyperoxic lung injury.