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Published ahead of print on June 12, 2003, doi:10.1165/rcmb.2003-0148OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 29, pp. 677-682, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2003-0148OC

Peroxisome Proliferator-Activated Receptor-{gamma} Is Deficient in Alveolar Macrophages from Patients with Alveolar Proteinosis

Tracey L. Bonfield, Carol F. Farver, Barbara P. Barna, Anagha Malur, Susamma Abraham, Baisakhi Raychaudhuri, Mani S. Kavuru and Mary Jane Thomassen

Departments of Pulmonary and Critical Care Medicine, Anatomic Pathology, and Cell Biology, The Cleveland Clinic Foundation, Cleveland, Ohio

Address correspondence to: Dr. Mary Jane Thomassen, Department of Pulmonary and Critical Care Medicine, 9500 Euclid Avenue, Cleveland Clinic Foundation, Desk A90, Cleveland, OH 44195-5038. E-mail: thomasm{at}ccf.org

Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) is a ligand-activated, nuclear transcription factor that regulates genes involved in lipid and glucose metabolism, inflammation, and other pathways. The hematopoietic growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF), is essential for lung homeostasis and is thought to regulate surfactant clearance, but mechanisms involved are unknown. GM-CSF is reported to stimulate PPAR-{gamma}, but the activation status of PPAR-{gamma} in human alveolar macrophages has not been defined. In pulmonary alveolar proteinosis (PAP), a rare interstitial lung disease, surfactant accumulates in alveolar airspaces, resident macrophages become engorged with lipoproteinaceous material, and GM-CSF deficiency is strongly implicated in pathogenesis. Here we show that PPAR-{gamma} mRNA and protein are highly expressed in alveolar macrophages of healthy control subjects but severely deficient in PAP in a cell-specific manner. Further, we show that the PPAR-{gamma}–regulated lipid scavenger receptor, CD36, is also deficient in PAP. PPAR-{gamma} and CD36 deficiency are not intrinsic to PAP alveolar macrophages, but can be upregulated by GM-CSF therapy. Moreover, GM-CSF treatment of patients with PAP fully restores PPAR-{gamma} to healthy control levels. Based upon these novel findings, we hypothesize that GM-CSF regulates lung homeostasis via PPAR-{gamma}–dependent pathways.

Abbreviations: granulocyte macrophage colony-stimulating factor, GM-CSF • interleukin, IL • pulmonary alveolar proteinosis, PAP • peroxisome proliferator-activated receptor-{gamma}, PPAR-{gamma}




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