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

Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis.

Author information

1
Translational Pulmonary Science Center, Children's Hospital Medical Center, Cincinnati, OH, USA.
2
Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, OH, USA.
3
Division of Pulmonary Medicine, Children's Hospital Medical Center, Cincinnati, OH, USA.
4
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
5
Division of Pulmonary and Critical Care Medicine, University of California Los Angeles, Los Angeles, CA, USA.
6
Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
7
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
8
Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. etarling@mednet.ucla.edu.
9
Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. etarling@mednet.ucla.edu.
10
Translational Pulmonary Science Center, Children's Hospital Medical Center, Cincinnati, OH, USA. Bruce.Trapnell@cchmc.org.
11
Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, OH, USA. Bruce.Trapnell@cchmc.org.
12
Division of Pulmonary Medicine, Children's Hospital Medical Center, Cincinnati, OH, USA. Bruce.Trapnell@cchmc.org.
13
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Bruce.Trapnell@cchmc.org.

Abstract

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.

PMID:
30087322
PMCID:
PMC6081448
DOI:
10.1038/s41467-018-05491-z
[Indexed for MEDLINE]
Free PMC Article

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