Restoration of PPAR gamma reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice

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.