Monocyte-Derived Alveolar Macrophages in ALI/ARDS: The Core Drivers of Inflammation.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a deadly disorder with poor therapeutic opportunities, driven by dysregulated immunity. Here we position monocyte-derived alveolar macrophages (Mo-AMs) as central mediators of ALI/ARDS pathogenesis, contrasting with homeostatic tissue-resident alveolar macrophages (TR-AMs). This review first traces the origin pathway of Mo-AMs, which differentiate from haematopoietic stem cells (HSCs) in the bone marrow and are recruited to the inflamed lung via a CCR2/CCL2-dependent pathway, ultimately differentiating into pathogenic effector cells within the alveolar microenvironment. Subsequently, we elucidate their primary pathogenic mechanisms: Mo-AMs mediate critical pathological injury by generating cytokine storms, depleting TR-AMs, disrupting the alveolar-capillary barrier and promoting fibrotic remodelling. Given their well-defined pathogenic role, Mo-AMs have emerged as a promising therapeutic target. Therefore, we conclude by reviewing recent advances in strategies targeting Mo-AMs, primarily encompassing the inhibition of their recruitment, induction of their apoptosis and reprogramming of their proinflammatory functions. These approaches collectively provide valuable insights for developing novel therapies for ALI/ARDS.