Pulmonary Alveolar Proteinosis: Rethinking Surfactant Homeostasis Through Alveolar Macrophage Lipid-Handling Dysfunction

Pulmonary alveolar proteinosis is a rare lung disease characterized by the accumulation of surfactant lipids and proteins within the alveolar space, leading to impaired gas exchange and progressive respiratory dysfunction. In most cases, pulmonary alveolar proteinosis arises from disruption of GM-CSF (granulocyte-macrophage colony-stimulating factor) signaling, resulting in defective alveolar macrophage maturation and a failure of surfactant clearance. Emerging work has reframed pulmonary alveolar proteinosis as a disorder of macrophage lipid handling, linking impaired cholesterol efflux and surfactant catabolism to both disease initiation and progression. In this review, we synthesize current understanding of pulmonary alveolar proteinosis pathophysiology, highlighting GM-CSF-dependent regulation of alveolar macrophage function, insights from animal and cellular models, and the evolving therapeutic landscape. We further discuss how targeting macrophage lipid homeostasis may offer new disease-modifying strategies.