UCLA

Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome that has no cure and no FDA approved therapies. It is characterized by the accumulation of surfactant within alveoli due to disruption of granulocyte-macrophage colony stimulating factor (GM-CSF) signaling. The pathogenic mechanism that underlies PAP remains unknown. Early studies suggested that PAP resulted from dysfunction in phospholipid homeostasis that led to the accumulation of phospholipid-enriched surfactant. However, more recent studies suggest that PAP pathogenesis is driven by changes in cholesterol homeostasis that may be linked to alveolar macrophages. The goal of this dissertation is to investigate the molecular mechanisms that lead to lipid dysregulation in PAP. First, we examined the lipid content of both alveolar macrophages and type 2 epithelial cells, two primary cells involved in surfactant homeostasis in a mouse model of PAP (Abcg1–/– mice). Compared to wildtype animals, Abcg1–/– mice had increased lipid deposition in both alveolar macrophages and type 2 epithelial cells, suggesting both cells are involved in the pathogenesis of PAP. Next, we observed that PAP patients who were treated with a cholesterol-lowering agent, statin, demonstrated improvements in their lung disease. We then treated Csf2rb–/– mice, another PAP mouse model, with a statin and found that they had improvement in their lung disease due to increased efflux of cholesterol from alveolar macrophages. Finally, we utilized lipidomic analysis and mass spectrometry to measure lipid composition of PAP alveolar macrophages. We found that compared to non-PAP alveolar macrophages, PAP alveolar macrophages were enriched in phosphatidylcholine (PC) and cholesterol ester (CE). Furthermore, clinical improvement in treated PAP patients was associated with a decrease in PC and CE classes, indicating that levels of these lipids correlated with the severity of the disease. Our studies demonstrate that disruption of both phospholipid and cholesterol homeostasis contributes to the pathogenesis of PAP. This new mechanistic insight has provided us with a better understanding of the pathophysiology of PAP and will be instrumental in our endeavor to find novel therapeutic targets and ultimately a cure for these patients.