The salutary effects of zinc supplementation on alveolar macrophage immune function can plausibly be linked to restoration of GM-CSF signaling through its master transcription factor PU.1. Specifically, we determined previously that GM-CSF signaling appears to be targeted in the alcoholic lung (Joshi et al., 2006;Joshi et al., 2005;Pelaez et al., 2004), and that dietary zinc supplementation in alcohol-fed rats restored phagocytic function to the alveolar macrophage in vitro (Joshi et al., 2008). These findings are consistent with earlier recognition that GM-CSF signaling is absolutely required for normal alveolar macrophage maturation and function (Shibata et al., 2001;Trapnell and Whitsett, 2002), and that its receptor-triggered signaling is mediated by its master transcription factor, PU.1. GM-CSF was first discovered in mouse lung extracts and found to be primarily secreted by alveolar epithelial type II cells (Shibata et al., 2001;Trapnell and Whitsett, 2002). The chief function of GM-CSF in facilitating the terminal differentiation of circulating monocytes into mature alveolar macrophages was discovered after development of the GM-CSF knockout mouse, which had normal bone marrow maturation, but abnormal alveolar macrophage maturation and a phenotype that
