Targeting cholesterol homeostasis in lung diseases.
Sci Rep
; 7(1): 10211, 2017 08 31.
Article
em En
| MEDLINE
| ID: mdl-28860566
ABSTRACT
Macrophages are critical to organ structure and function in health and disease. To determine mechanisms by which granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling normally maintains surfactant homeostasis and how its disruption causes pulmonary alveolar proteinosis (PAP), we evaluated lipid composition in alveolar macrophages and lung surfactant, macrophage-mediated surfactant clearance kinetics/dynamics, and cholesterol-targeted pharmacotherapy of PAP in vitro and in vivo. Without GM-CSF signaling, surfactant-exposed macrophages massively accumulated cholesterol ester-rich lipid-droplets and surfactant had an increased proportion of cholesterol. GM-CSF regulated cholesterol clearance in macrophages in constitutive, dose-dependent, and reversible fashion but did not affect phospholipid clearance. PPARγ-agonist therapy increased cholesterol clearance in macrophages and reduced disease severity in PAP mice. Results demonstrate that GM-CSF is required for cholesterol clearance in macrophages, identify reduced cholesterol clearance as the primary macrophage defect driving PAP pathogenesis, and support the feasibility of translating pioglitazone as a novel pharmacotherapy of PAP.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteinose Alveolar Pulmonar
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Colesterol
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Fator Estimulador de Colônias de Granulócitos e Macrófagos
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Pioglitazona
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article