GM-CSF receptor expression and signaling is decreased in lungs of ethanol-fed rats.
Alcohol abuse dramatically increases the risk of acute lung injury. In an experimental rat model of ethanol-mediated susceptibility to lung injury, recombinant granulocyte/macrophage colony-stimulating factor (GM-CSF) restored alveolar epithelial barrier function both in vitro and in vivo, even during acute endotoxemia. These findings suggested that the alveolar epithelium, which secretes GM-CSF into the airway where it is required for alveolar macrophage maturation, likewise responds to GM-CSF priming in a receptor-mediated manner. In this study we determined that both the GM-CSF receptor alpha- and beta-subunits (GM-CSFRalpha and GM-CSFRbeta) are expressed throughout the rat airway epithelium and that this expression was significantly decreased in the alveolar epithelium following chronic ethanol ingestion (6 wk). In parallel, PU.1, the master transcription factor for GM-CSF signaling in hematopoietic cells, is also expressed in alveolar epithelial cells, and ethanol ingestion likewise decreased PU.1 protein expression and nuclear binding in the alveolar epithelium. Finally, GM-CSF signaling as reflected by PU.1 expression and nuclear binding was restored with recombinant GM-CSF treatment in vitro. We conclude that chronic ethanol ingestion decreases GM-CSF receptor expression and signaling in the lung epithelium. Consequently, we speculate that dampening of GM-CSF stimulation of the alveolar epithelium is responsible at least in part for the diverse functional defects that characterize the alcoholic lung and could be a therapeutic target in acute lung injury.
Joshi
Pratibha C
PC
Atlanta Veterans Affairs Medical Center, Emory University School of Medicine, Atlanta, Georgia 30033, USA. pcjoshi@emory.edu
Applewhite
Lisa
L
Mitchell
Patrick O
PO
Fernainy
Khaled
K
Roman
Jesse
J
Eaton
Douglas C
DC
Guidot
David M
DM
D000437:Alcoholism; D000818:Animals; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011650:Pulmonary Alveoli / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000502:physiology* / Q000503:physiopathology; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011518:Proto-Oncogene Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1