Targeting cholesterol homeostasis in lung diseases

Sci Rep. 2017 Aug 31;7(1):10211. doi: 10.1038/s41598-017-10879-w.


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. PPARγ-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cholesterol / metabolism*
  • Disease Models, Animal
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • Homeostasis / drug effects
  • Humans
  • Macrophages, Alveolar / cytology
  • Macrophages, Alveolar / metabolism
  • Mice
  • PPAR gamma / agonists
  • Pioglitazone / administration & dosage*
  • Pioglitazone / pharmacology
  • Pulmonary Alveolar Proteinosis / drug therapy*
  • Pulmonary Alveolar Proteinosis / metabolism
  • Signal Transduction / drug effects


  • PPAR gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Cholesterol
  • Pioglitazone