Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 300, Issue 1, Pages L73-L80Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00128.2010
Keywords
ATP-binding cassette transporter G1; foam cells; surfactant
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Funding
- North Carolina Biotechnology Center [2005-FFRG-1013]
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Malur A, Baker AD, Mccoy AJ, Wells G, Barna BP, Kavuru MS, Malur AG, Thomassen MJ. Restoration of PPAR gamma reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice. Am J Physiol Lung Cell Mol Physiol 300: L73-L80, 2011. First published October 29, 2010; doi:10.1152/ajplung.00128.2010.-Pulmonary alveolar proteinosis (PAP) is a lung disease characterized by a deficiency of functional granulocyte macrophage colony-stimulating factor (GM-CSF) resulting in surfactant accumulation and lipid-engorged alveolar macrophages. GM-CSF is a positive regulator of PPAR gamma that is constitutively expressed in healthy alveolar macrophages. We previously reported decreased PPAR gamma and ATP-binding cassette transporter G1 (ABCG1) levels in alveolar macrophages from PAP patients and GM-CSF knockout (KO) mice, suggesting PPAR gamma and ABCG1 involvement in surfactant catabolism. Because ABCG1 represents a PPAR gamma target, we hypothesized that PPAR gamma restoration would increase ABCG1 and reduce macrophage lipid accumulation. Upregulation of PPAR gamma was achieved using a lentivirus expression system in vivo. GM-CSF KO mice received intratracheal instillation of lentivirus (lenti)-PPAR gamma or control lenti-eGFP. Ten days post-instillation, 79% of harvested alveolar macrophages expressed eGFP, demonstrating transduction. Alveolar macrophages showed increased PPAR gamma and ABCG1 expression after lenti-PPAR gamma instillation, whereas PPAR gamma and ABCG1 levels remained unchanged in lenti-eGFP controls. Alveolar macrophages from lenti-PPAR gamma-treated mice also exhibited reduced intracellular phospholipids and increased cholesterol efflux to HDL, an ABCG1-mediated pathway. In vivo instillation of lenti-PPAR gamma results in: 1) upregulating ABCG1 and PPAR gamma expression of GM-CSF KO alveolar macrophages, 2) reducing intracellular lipid accumulation, and 3) increasing cholesterol efflux activity.
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