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Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis

Author

Listed:
  • Cormac McCarthy

    (Children’s Hospital Medical Center
    Children’s Hospital Medical Center
    Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Elinor Lee

    (University of California Los Angeles
    University of California Los Angeles)

  • James P. Bridges

    (Children’s Hospital Medical Center)

  • Anthony Sallese

    (Children’s Hospital Medical Center
    Children’s Hospital Medical Center)

  • Takuji Suzuki

    (Children’s Hospital Medical Center
    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
    University of California Los Angeles)

  • Claudia Chalk

    (Children’s Hospital Medical Center
    Children’s Hospital Medical Center)

  • Brenna C. Carey

    (Children’s Hospital Medical Center
    Children’s Hospital Medical Center)

  • Paritha Arumugam

    (Children’s Hospital Medical Center
    Children’s Hospital Medical Center)

  • Kenjiro Shima

    (Children’s Hospital Medical Center
    Children’s Hospital Medical Center)

  • Elizabeth J. Tarling

    (University of California Los Angeles
    University of California Los Angeles)

  • Bruce C. Trapnell

    (Children’s Hospital Medical Center
    Children’s Hospital Medical Center
    Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

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.

Suggested Citation

  • 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 Shi, 2018. "Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05491-z
    DOI: 10.1038/s41467-018-05491-z
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    Cited by:

    1. Michal Scur & Ahmad Bakur Mahmoud & Sayanti Dey & Farah Abdalbarri & Iona Stylianides & Daniel Medina-Luna & Gayani S. Gamage & Aaron Woblistin & Alexa N. M. Wilson & Haggag S. Zein & Ashley Stueck & , 2022. "Alveolar macrophage metabolic programming via a C-type lectin receptor protects against lipo-toxicity and cell death," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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