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1 Pulmonary Section, Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA; The Division of Pulmonary, Allergy, & Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
2 Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
* To whom correspondence should be addressed. E-mail: dguidot{at}emory.edu.
Chronic alcohol abuse increases the risk of developing acute lung injury ~ 3-fold in septic patients, and ethanol ingestion for 6 weeks in rats impairs alveolar epithelial barrier function both in vitro and in vivo. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a trophic factor for the alveolar epithelium and a recent phase II clinical study suggests that GM-CSF therapy decreases sepsis-mediated lung injury. Therefore, we hypothesized that GM-CSF treatment could improve ethanol-mediated defects in the alveolar epithelium during acute stresses such as endotoxemia. In this study we determined that recombinant rat GM-CSF (500 ng intranasally x 3 days) improved (p<0.05) lung liquid clearance (as reflected by lung tissue wet:dry ratios) in ethanol-fed rats anesthetized and then challenged with 2 cc of saline via a tracheostomy tube. Further, GM-CSF treatment improved (p<0.05) lung liquid clearance, and decreased (p<0.05) epithelial protein leak, in both control-fed and ethanol-fed rats following 6 hours of endotoxemia induced by S. typhimurium lipopolysaccharide given intraperitoneally, but with the greater net effect seen in the ethanol-fed rats. Our previous studies indicate that chronic ethanol ingestion decreases lung liquid clearance by increasing intercellular permeability. Consistent with this, GM-CSF treatment in vitro decreased (p<0.05) permeability of alveolar epithelial monolayers derived from both control-fed and ethanol-fed rats. As in the endotoxemia model in vivo, the effect of GM-CSF was most dramatic in the ethanol group. Taken together, these results indicate that GM-CSF treatment has previously unrecognized effects in promoting alveolar epithelial barrier integrity, and that these salutary effects may be particularly relevant in the setting of chronic alcohol abuse.
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