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 pathway as reflected by deceased Nrf2 nuclear binding and antioxidant gene expression in alveolar macrophages from alcohol-fed rats. In fact, it is possible that the alcohol-induced lung oxidative stress that we have identified and characterized in this population is caused by zinc deficiency and impaired antioxidant defenses rather than a primary increase in oxidant production. Interestingly, there is also evidence that zinc depletion alone creates a state of oxidative stress in the lungs and airways (Zalewski, 2006). These studies emphasize the importance of zinc itself in the antioxidant response. In any case, zinc supplementation—either in vitro or in vivo—restored Nrf2 nuclear binding. To further investigate Nrf2 induction of ARE activation, we also evaluated the ARE-inducible gene metallothionein, which did show decreased expression with alcohol and restoration with zinc supplementation. Indeed, dietary zinc supplementation in alcohol-fed rats decreased oxidative stress and restored redox balance in the lungs. Taken together, these findings highlight the role of dietary zinc in mitigating the effects
