| First Author | Malur A | Year | 2011 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 300 |
| Issue | 1 | Pages | L73-80 |
| PubMed ID | 21036914 | Mgi Jnum | J:168397 |
| Mgi Id | MGI:4888159 | Doi | 10.1152/ajplung.00128.2010 |
| Citation | Malur A, et al. (2011) Restoration of PPARgamma reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice. Am J Physiol Lung Cell Mol Physiol 300(1):L73-80 |
| abstractText | 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 PPARgamma that is constitutively expressed in healthy alveolar macrophages. We previously reported decreased PPARgamma and ATP-binding cassette transporter G1 (ABCG1) levels in alveolar macrophages from PAP patients and GM-CSF knockout (KO) mice, suggesting PPARgamma and ABCG1 involvement in surfactant catabolism. Because ABCG1 represents a PPARgamma target, we hypothesized that PPARgamma restoration would increase ABCG1 and reduce macrophage lipid accumulation. Upregulation of PPARgamma was achieved using a lentivirus expression system in vivo. GM-CSF KO mice received intratracheal instillation of lentivirus (lenti)-PPARgamma or control lenti-eGFP. Ten days postinstillation, 79% of harvested alveolar macrophages expressed eGFP, demonstrating transduction. Alveolar macrophages showed increased PPARgamma and ABCG1 expression after lenti-PPARgamma instillation, whereas PPARgamma and ABCG1 levels remained unchanged in lenti-eGFP controls. Alveolar macrophages from lenti-PPARgamma-treated mice also exhibited reduced intracellular phospholipids and increased cholesterol efflux to HDL, an ABCG1-mediated pathway. In vivo instillation of lenti-PPARgamma results in: 1) upregulating ABCG1 and PPARgamma expression of GM-CSF KO alveolar macrophages, 2) reducing intracellular lipid accumulation, and 3) increasing cholesterol efflux activity. |
