Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis

Cormac McCarthy, Elinor Lee, James P. Bridges, Anthony Sallese, Takuji Suzuki, Jason C. Woods, Brian Jack Bartholmai, Tisha Wang, Claudia Chalk, Brenna C. Carey, Paritha Arumugam, Kenjiro Shima, Elizabeth J. Tarling, Bruce C. Trapnell

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Article number3127
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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Pulmonary Alveolar Proteinosis
Drug therapy
Hydroxymethylglutaryl-CoA Reductase Inhibitors
macrophages
Alveolar Macrophages
cholesterol
Surface-Active Agents
Cholesterol
Drug Therapy
Macrophages
surfactants
pathogenesis
Phospholipids
therapy
Therapeutics
Granulocyte-Macrophage Colony-Stimulating Factor
efflux
Respiratory Insufficiency
clearances
Lipids

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

McCarthy, C., Lee, E., Bridges, J. P., Sallese, A., Suzuki, T., Woods, J. C., ... Trapnell, B. C. (2018). Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis. Nature Communications, 9(1), [3127]. https://doi.org/10.1038/s41467-018-05491-z

Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis. / McCarthy, Cormac; Lee, Elinor; Bridges, James P.; Sallese, Anthony; Suzuki, Takuji; Woods, Jason C.; Bartholmai, Brian Jack; Wang, Tisha; Chalk, Claudia; Carey, Brenna C.; Arumugam, Paritha; Shima, Kenjiro; Tarling, Elizabeth J.; Trapnell, Bruce C.

In: Nature Communications, Vol. 9, No. 1, 3127, 01.12.2018.

Research output: Contribution to journalArticle

McCarthy, C, Lee, E, Bridges, JP, Sallese, A, Suzuki, T, Woods, JC, Bartholmai, BJ, Wang, T, Chalk, C, Carey, BC, Arumugam, P, Shima, K, Tarling, EJ & Trapnell, BC 2018, 'Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis', Nature Communications, vol. 9, no. 1, 3127. https://doi.org/10.1038/s41467-018-05491-z
McCarthy C, Lee E, Bridges JP, Sallese A, Suzuki T, Woods JC et al. Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis. Nature Communications. 2018 Dec 1;9(1). 3127. https://doi.org/10.1038/s41467-018-05491-z
McCarthy, Cormac ; Lee, Elinor ; Bridges, James P. ; Sallese, Anthony ; Suzuki, Takuji ; Woods, Jason C. ; Bartholmai, Brian Jack ; Wang, Tisha ; Chalk, Claudia ; Carey, Brenna C. ; Arumugam, Paritha ; Shima, Kenjiro ; Tarling, Elizabeth J. ; Trapnell, Bruce C. / Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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