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Published ahead of print on June 12, 2003, doi:10.1165/rcmb.2003-0148OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 6, December 2003, 677-682

A more recent version of this article appeared on December 1, 2003
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Submitted on April 28, 2003
Revised on June 12, 2003

PPAR-{gamma} is Deficient in Alveolar Macrophages from Patients with Alveolar Proteinosis

Tracey L Bonfield1, Carol F Farver2, Barbara P Barna1, Anagha Malur1, Susamma Abraham1, Baisakhi Raychaudhuri1, Mani S Kavuru1, and Mary Jane Thomassen3*

1 Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA, 2 Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA; Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA, 3 Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA; Cell Biology, Cleveland Clinic Foundation, Cleveland, OH, USA

* To whom correspondence should be addressed. 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 controls 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 up-regulated by GM-CSF therapy. Moreover, GM-CSF treatment of PAP patients 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.




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