Chronic ethanol abuse leads to increased susceptibility to acute lung injury (ALI) and mortality in the setting of sepsis. We believe that this is due, in part, to alterations in the expression of tissue remodeling genes that prime the lung to disrepair after injury. This is supported by our own findings showing that lungs harvested from rodents treated with ethanol show increased expression of fibronectin, matrix metalloproteinases, and transforming growth factor β; we also demonstrated activation of matrix remodeling in alcoholics. Together with changes in oxidative stress and epithelial cell dysfunction, these alterations represent key features of what has been termed the “alcoholic lung phenotype”. Despite the above advances, we still do not understand the mechanisms that lead to these changes nor the role of matrix remodeling in the alcoholic lung. Importantly, the mechanisms by which these changes render the lung susceptible to disrepair after injury remain unclear. We hypothesize that chronic ethanol promotes redox stress that triggers extracellular matrix (ECM) remodeling resulting in the `re-pavement' of the lung with a `pro-inflammatory' ECM characterized by increased expression of fibronectin EDA and collagen V, two molecules implicated in tissue disrepair. Upon injury of the alcoholic lung, epithelial cells trying to populate denuded areas become exposed to this “aberrant” ECM resulting in increased permeability, while incoming immune cells exposed to this ECM experience exaggerated activation. Together, these processes enhance inflammation and epithelial cell dysfunction leading to disrepair and, ultimately, ALI. We have observed similar derangements in the aging lung and speculate that ethanol-induced redox stress promotes accelerated aging of the lung through epigenetic modifications that drive ECM remodeling. Our hypothesis is supported by several in vivo studies demonstrating a role for the ECM in the lung's response to injury. Second, we showed that primary lung cells harvested from ethanol-treated animals deposit a pro-inflammatory matrix. Third, we found that alveolar epithelial cells cultured on different matrices show alterations in their expression of claudins resulting in barrier dysfunction. Fourth, like ethanol, we found that aging also promotes ECM remodeling and this defect is associated with epigenetic histone modifications that drive fibronectin gene expression; we speculate that similar mechanisms are taking place here. Finally, recent studies in our laboratory suggest that the above effects might be dependent on ethanol-induced redox stress and could potentially be ameliorated by dietary interventions targeting redox stress. We aim to test the hypothesis in specific aims designed to: 1) Examine the effects of ethanol-induced ECM remodeling on immune cells and epithelial cells in vitro and explore its role in susceptibility to ALI in vivo; 2) Examine ethanol- dependent, gene-specific, promoter-associated epigenetic modifications regulating ECM gene expression in lung fibroblasts; and 3) Investigate how ethanol-induced redox stress promotes ECM remodeling, and determine the effect of anti-oxidant dietary interventions on ethanol-induced ECM remodeling and susceptibility to ALI.