Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis

Nat Commun. 2018 Aug 7;9(1):3127. doi: 10.1038/s41467-018-05491-z.


Pulmonary alveolar proteinosis (PAP) is a syndrome of reduced GM-CSF-dependent, macrophage-mediated surfactant clearance, dysfunctional foamy alveolar macrophages, alveolar surfactant accumulation, and hypoxemic respiratory failure for which the pathogenetic mechanism is unknown. Here, we examine the lipids accumulating in alveolar macrophages and surfactant to define the pathogenesis of PAP and evaluate a novel pharmacotherapeutic approach. In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids. Oral statin therapy is associated with clinical, physiological, and radiological improvement in autoimmune PAP patients, and ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages. In Csf2rb-/- mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages. These results support the feasibility of statin as a novel pathogenesis-based pharmacotherapy of PAP.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Animals
  • Bronchoalveolar Lavage
  • Cholesterol / metabolism
  • Cytokine Receptor Common beta Subunit / genetics
  • Female
  • Gene Expression Profiling
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Lipids / chemistry
  • Lung Diseases / diagnostic imaging
  • Macrophages, Alveolar / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Pulmonary Alveolar Proteinosis / drug therapy*
  • Pulmonary Alveolar Proteinosis / genetics
  • Pulmonary Alveolar Proteinosis / immunology
  • Pulmonary Surfactants / therapeutic use
  • Surface-Active Agents
  • Tomography, X-Ray Computed


  • Cytokine Receptor Common beta Subunit
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipids
  • Pulmonary Surfactants
  • Surface-Active Agents
  • Csf2rb protein, mouse
  • Cholesterol