Alcohol is one of the most commonly abused drugs in the world. In the intensive care unit (ICU), patients with a history of alcohol abuse are common, and their rates of mortality and morbidity are significantly higher when compared to patients with no prior history of alcohol abuse. Though ICU patients are a heterogeneous group, Acute Respiratory Distress Syndrome (ARDS), a devastating form of acute lung injury, is one of the more frequent diagnoses among these critically ill patients. Our group has pioneered the clinical research concerning the association between alcohol abuse and ARDS. We have determined that chronic alcohol abuse significantly increases the risk of developing ARDS. This association is a common phenomenon as 50% of all ARDS patients had a prior history of alcohol abuse in our patient population. Though defined by the development of hypoxemia and diffuse bilateral infiltrates on chest radiograph in the absence of left atrial hypertension, ARDS is characterized by diffuse alveolar damage, increased pulmonary alveolar capillary permeability, and the subsequent accumulation of extravascular lung water. Using animal models of chronic alcohol abuse, we have determined that chronic ethanol ingestion alone produces oxidative stress and glutathione depletion within the alveolar space and impairs alveolar-capillary barrier function. We hypothesize that alterations in alveolar capillary barrier function that are associated with decreased pulmonary glutathione concentrations will be present in humans with a history of chronic alcohol abuse. Similarly, we expect that a prior history of chronic alcohol abuse will be associated with enhanced defects in the alveolar capillary permeability in critically ill patients with ARDS. In addition, we hypothesize that oral glutathione replacement therapy will correct these deficiencies in alveolar capillary barrier function, thereby establishing a causal relationship between glutathione deficiency and alveolar capillary permeability in individuals with a history of chronic alcohol abuse. More importantly, this work will identify glutathione replacement therapy as a prophylactic therapy for the many alcoholic patients who may be at risk for the development of ARDS, and establish the important precedent for the potential use of glutathione replacement therapy for alcohol-associated ARDS patients ? ?
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