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.

Details

Title
Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis
Author
McCarthy, Cormac 1 ; Lee, Elinor 2 ; Bridges, James P 3 ; Sallese, Anthony 4 ; Suzuki, Takuji 4 ; Woods, Jason C 5 ; Bartholmai, Brian J 6   VIAFID ORCID Logo  ; Wang, Tisha 2 ; Chalk, Claudia 4 ; Carey, Brenna C 4 ; Arumugam, Paritha 4 ; Shima, Kenjiro 4 ; Tarling, Elizabeth J 7   VIAFID ORCID Logo  ; Trapnell, Bruce C 1 

 Translational Pulmonary Science Center, Children’s Hospital Medical Center, Cincinnati, OH, USA; Division of Pulmonary Biology, Children’s Hospital Medical Center, Cincinnati, OH, USA; Division of Pulmonary Medicine, Children’s Hospital Medical Center, Cincinnati, OH, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA 
 Division of Pulmonary and Critical Care Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA 
 Division of Pulmonary Biology, Children’s Hospital Medical Center, Cincinnati, OH, USA 
 Translational Pulmonary Science Center, Children’s Hospital Medical Center, Cincinnati, OH, USA; Division of Pulmonary Biology, Children’s Hospital Medical Center, Cincinnati, OH, USA 
 Division of Pulmonary Medicine, Children’s Hospital Medical Center, Cincinnati, OH, USA 
 Department of Radiology, Mayo Clinic, Rochester, MN, USA 
 Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA 
Pages
1-9
Publication year
2018
Publication date
Aug 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2084901142
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.