TY - JOUR
T1 - Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis
AU - McCarthy, Cormac
AU - Lee, Elinor
AU - Bridges, James P.
AU - Sallese, Anthony
AU - Suzuki, Takuji
AU - Woods, Jason C.
AU - Bartholmai, Brian J.
AU - Wang, Tisha
AU - Chalk, Claudia
AU - Carey, Brenna C.
AU - Arumugam, Paritha
AU - Shima, Kenjiro
AU - Tarling, Elizabeth J.
AU - Trapnell, Bruce C.
N1 - Funding Information:
We thank our patients with PAP, without whose collaboration this work would not have been possible. This work was supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant numbers R01085453 (PI: B.C.T.), HL131634 (PI: J.P. B.), HL118161 and HL136543 (PI: E.J.T.) and National Center for Advancing Translational Science/National Heart, Lung, and Blood Institute grant number HL127672 (PI: B.C.T.).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-05491-z
DO - 10.1038/s41467-018-05491-z
M3 - Article
C2 - 30087322
AN - SCOPUS:85051164964
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3127
ER -