Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis

Cormac McCarthy, Elinor Lee, James P. Bridges, Anthony Sallese, Takuji Suzuki, Jason C. Woods, Brian J. Bartholmai, Tisha Wang, Claudia Chalk, Brenna C. Carey, Paritha Arumugam, Kenjiro Shima, Elizabeth J. Tarling () and Bruce C. Trapnell ()
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Cormac McCarthy: Children’s Hospital Medical Center
Elinor Lee: University of California Los Angeles
James P. Bridges: Children’s Hospital Medical Center
Anthony Sallese: Children’s Hospital Medical Center
Takuji Suzuki: Children’s Hospital Medical Center
Jason C. Woods: Children’s Hospital Medical Center
Brian J. Bartholmai: Mayo Clinic
Tisha Wang: University of California Los Angeles
Claudia Chalk: Children’s Hospital Medical Center
Brenna C. Carey: Children’s Hospital Medical Center
Paritha Arumugam: Children’s Hospital Medical Center
Kenjiro Shima: Children’s Hospital Medical Center
Elizabeth J. Tarling: University of California Los Angeles
Bruce C. Trapnell: Children’s Hospital Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05491-z

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