Targeting cholesterol homeostasis in lung diseases.

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.

• Authors: Anthony Sallese, Takuji Suzuki, Cormac McCarthy, James Bridges, Alyssa Filuta, Paritha Arumugam, Kenjiro Shima, Yan Ma, Matthew Wessendarp, Diane Black, Claudia Chalk, Brenna Carey, Bruce C Trapnell
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 10211 (08 31 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28860566 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• PPAR gamma
• Granulocyte-Macrophage Colony-Stimulating Factor
• Cholesterol
• Pioglitazone

Topics

• Animals
• Cell Differentiation (drug effects)
• Cholesterol (metabolism)
• Disease Models, Animal
• Granulocyte-Macrophage Colony-Stimulating Factor (pharmacology)
• Homeostasis (drug effects)
• Humans
• Macrophages, Alveolar (cytology, metabolism)
• Mice
• PPAR gamma (agonists)
• Pioglitazone (administration & dosage, pharmacology)
• Pulmonary Alveolar Proteinosis (drug therapy, metabolism)
• Signal Transduction (drug effects)