from our alcohol research group implicate a defect in signaling by granulocyte/monocyte colony-stimulating factor (GM-CSF), which is integral to macrophage maturation, differentiation and function. We determined that chronic alcohol ingestion decreases GM-CSF receptor expression and signaling capacity through its master transcription factor, PU.1, in both the alveolar macrophage and the alveolar epithelium (Joshi et al., 2006;Joshi et al., 2005). Importantly, treatment with recombinant GM-CSF via the airway rapidly (within 48 hrs) reverses alcohol-induced defects in alveolar epithelial barrier function, and GM-CSF treatment in vitro of alveolar epithelial cells and macrophages isolated from alcohol-fed rats restores signaling through PU.1 and normalizes barrier and immune function in these cells, respectively (Joshi et al., 2006;Joshi et al., 2005). Taken together, these experimental studies suggest that even otherwise “healthy” alcoholics may have diminished GM-CSF-dependent priming of the alveolar macrophage pool that leaves them poorly equipped to respond to infectious and inflammatory stimuli.
