REVISED ABSTRACT The alcohol research group at Emory University has determined that alcohol abuse increases the risk 3-fold of developing the Acute Respiratory Distress Syndrome (ARDS), a severe form of lung injury that kills tens of thousands of Americans each year. In fact, the Center's studies in nearly 600 patients indicate that ~50% of all patients who develop ARDS have a significant history of alcohol abuse. In addition, the Center's investigators have determined that ethanol-mediated depletion of the critical antioxidant glutathione produces specific defects in lung structure and function that render the lung susceptible to acute injury. ARDS is part of a spectrum of tissue injury in critically ill patients that has been termed the 'multiple organ dysfunction syndrome'. This syndrome produces devastating consequences in terms of mortality and prolonged morbidities in survivors. However, it does not arise de novo but rather in response to a variety of acute insults, such as trauma and sepsis. The important question is how does alcohol abuse render the lung and other organs susceptible to injury and failure in critically ill patients? The Center investigators hypothesize that alcohol abuse produces chronic oxidative stress within the lung, and that an array of consequent defects in lung structure and function render patients susceptible to respiratory failure and associated multiple organ dysfunction. Further, this mechanism affects infants born prematurely to mothers with a significant alcohol abuse history in addition to adults admitted to intensive care units for treatment of sepsis, trauma, or other critical illnesses. The proposed Emory Alcohol and Lung Biology Center will extend this previous work and dissect the clinical associations as well as the fundamental mechanisms underlying alcohol abuse and multiple organ dysfunction. Capitalizing on established collaborations as well as the talents of recently recruited faculty, the Center will test the central hypothesis in a comprehensive set of related projects that include in vitro and in vivo animal models, as well as clinical studies in pediatric and adult intensive care unit settings. The Center will conduct six collaborative research projects that examine the effects of ethanol on lung epithelial, endothelial, and matrix biology. In parallel, the Pilot Component will facilitate novel pilot projects that will identify new aspects of alcohol-mediated tissue injury in basic and clinical projects. Finally, the Center will nurture the training of scientists for careers in alcohol research. The work proposed by this Center has enormous implications for the understanding of the diagnosis and prognosis of hundreds of thousands of patients in intensive care units throughout the U.S., and could lead to the development of novel therapies for those patients at greatest risk for multiple organ dysfunction as a consequence of chronic alcohol abuse.
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