The Acute Respiratory Distress Syndrome (ARDS) is a common and severe form of lung injury with a mortality of approximately 50 percent. A prospective study of 351 critically ill patients recently identified that a history of chronic alcohol abuse increased the incidence and severity of ARDS regardless of the at-risk diagnosis. This observation distinguishes chronic alcohol abuse as the first reported co-morbid variable that significantly increases a patient's risk of developing ARDS and raises questions about the pathophysiology and specific treatment of acute lung injury. This project will test the hypothesis that chronic alcohol abuse decreases alveolar type II cell levels of glutathione, an important antioxidant, thereby impairing surfactant secretion and function and rendering the lung susceptible to injury. In ARDS the alveolar type II cells are severely damaged, and their ability to secrete glutathione and surfactant into the alveolar lining fluid are critical to patient survival. Because sepsis is the most common risk factor for ARDS, this project will focus on the sepsis syndrome in both patients and in an animal model. Preliminary studies presented in this proposal show that chronic alcohol ingestion in rats decreases type II cell glutathione levels and, in parallel, decreases type II cell surfactant secretion both in vitro and in vivo, and predisposes to endotoxin-mediated acute lung injury. In addition, we determined that otherwise healthy alcoholics have markedly decreased levels of glutathione in their lung lavage fluid compared to control subjects. The fundamental mechanisms by which chronic alcohol use affects alveolar epithelial function will be examined in a rat model of sepsis in vivo and in isolated type II cells in vitro. Parallel clinical studies in both healthy subjects and in critically ill patients with sepsis will examine the effects of chronic alcohol abuse on lung glutathione homeostasis and surfactant production both in isolated type II cells and in lung lavage fluid. We will thereby test the clinical relevance of the fundamental mechanisms elucidated in the animal model. Importantly, our preliminary studies indicate that glutathione replacement can decrease ethanol-mediated lung injury in our animal model, and this project will ultimately focus on developing a glutathione replacement regimen that reduces the harmful effects of chronic alcohol ingestion on the lungs of patients.
| Fan, Xian; Joshi, Pratibha C; Koval, Michael et al. (2011) Chronic alcohol ingestion exacerbates lung epithelial barrier dysfunction in HIV-1 transgenic rats. Alcohol Clin Exp Res 35:1866-75 |
| Quintero, David; Guidot, David M (2010) Focus on the lung. Alcohol Res Health 33:219-28 |
| Joshi, Pratibha C; Mehta, Ashish; Jabber, Wissam S et al. (2009) Zinc deficiency mediates alcohol-induced alveolar epithelial and macrophage dysfunction in rats. Am J Respir Cell Mol Biol 41:207-16 |
| Joshi, Pratibha C; Raynor, Robert; Fan, Xian et al. (2008) HIV-1-transgene expression in rats decreases alveolar macrophage zinc levels and phagocytosis. Am J Respir Cell Mol Biol 39:218-26 |
| Danai, Pajman A; Sinha, Sumita; Moss, Marc et al. (2007) Seasonal variation in the epidemiology of sepsis. Crit Care Med 35:410-5 |
| Martin, Greg S; Mannino, David M; Moss, Marc (2006) The effect of age on the development and outcome of adult sepsis. Crit Care Med 34:15-21 |
| Danai, Pajman A; Moss, Marc; Mannino, David M et al. (2006) The epidemiology of sepsis in patients with malignancy. Chest 129:1432-40 |
| Esper, Annette M; Moss, Marc; Lewis, Charmaine A et al. (2006) The role of infection and comorbidity: Factors that influence disparities in sepsis. Crit Care Med 34:2576-82 |
| Martin, Greg S; Eaton, Stephanie; Mealer, Meredith et al. (2005) Extravascular lung water in patients with severe sepsis: a prospective cohort study. Crit Care 9:R74-82 |
| Martin, Greg S; Moss, Marc; Wheeler, Arthur P et al. (2005) A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med 33:1681-7 |
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