A novel finding in this study is that there appear to be remarkably parallel zinc-dependent effects on Nrf2, the master transcription factor for the antioxidant response element (ARE). Similar to its effects on PU.1 and the GM-CSF pathway, zinc supplementation restored Nrf2 nuclear binding in the alveolar macrophage, and this was reflected in improvement of the redox balance in cysteine and cystine within the alveolar space. This is important since one of the major cellular consequences of alcoholism is increased oxidative stress, which has many implications and contributes significantly to the overall alcoholic lung phenotype (Guidot and Hart, 2005;Joshi and Guidot, 2007). Further, despite the oxidative stress, the alcoholic lung appears to respond inadequately in activating its antioxidant defenses. The ARE is a gene program that is a critical defense against oxidative stress through transcription of antioxidant genes (Nguyen et al., 2003). Nrf2 plays an important role in transcriptional activation of ARE-driven genes similar to the role of PU.1 in the GM-CSF pathway. In parallel to the GM-CSF pathway, our studies provide evidence that alcohol interferes with the ARE signaling
