| First Author | Sallese A | Year | 2017 |
| Journal | Sci Rep | Volume | 7 |
| Issue | 1 | Pages | 10211 |
| PubMed ID | 28860566 | Mgi Jnum | J:256487 |
| Mgi Id | MGI:6108517 | Doi | 10.1038/s41598-017-10879-w |
| Citation | Sallese A, et al. (2017) Targeting cholesterol homeostasis in lung diseases. Sci Rep 7(1):10211 |
| abstractText | Macrophages are critical to organ structure and function in health and disease. To determine mechanisms by which granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling normally maintains surfactant homeostasis and how its disruption causes pulmonary alveolar proteinosis (PAP), we evaluated lipid composition in alveolar macrophages and lung surfactant, macrophage-mediated surfactant clearance kinetics/dynamics, and cholesterol-targeted pharmacotherapy of PAP in vitro and in vivo. Without GM-CSF signaling, surfactant-exposed macrophages massively accumulated cholesterol ester-rich lipid-droplets and surfactant had an increased proportion of cholesterol. GM-CSF regulated cholesterol clearance in macrophages in constitutive, dose-dependent, and reversible fashion but did not affect phospholipid clearance. PPARgamma-agonist therapy increased cholesterol clearance in macrophages and reduced disease severity in PAP mice. Results demonstrate that GM-CSF is required for cholesterol clearance in macrophages, identify reduced cholesterol clearance as the primary macrophage defect driving PAP pathogenesis, and support the feasibility of translating pioglitazone as a novel pharmacotherapy of PAP. |
