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 ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA014435-06
Application #
7433949
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Jung, Kathy
Project Start
2004-06-01
Project End
2010-11-30
Budget Start
2008-06-01
Budget End
2010-11-30
Support Year
6
Fiscal Year
2008
Total Cost
$328,545
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Burnham, Ellen L; Phang, Tzu L; House, Robert et al. (2011) Alveolar macrophage gene expression is altered in the setting of alcohol use disorders. Alcohol Clin Exp Res 35:284-94
Burnham, Ellen L; Gaydos, Jeanette; Hess, Edward et al. (2010) Alcohol use disorders affect antimicrobial proteins and anti-pneumococcal activity in epithelial lining fluid obtained via bronchoalveolar lavage. Alcohol Alcohol 45:414-21
Burnham, Ellen L; Halkar, Raghuveer; Burks, Marsha et al. (2009) The effects of alcohol abuse on pulmonary alveolar-capillary barrier function in humans. Alcohol Alcohol 44:8-12
Berkowitz, David M; Danai, Pajman A; Eaton, Stephanie et al. (2009) Alcohol abuse enhances pulmonary edema in acute respiratory distress syndrome. Alcohol Clin Exp Res 33:1690-6
Yeh, Mary Y; Burnham, Ellen L; Moss, Marc et al. (2008) Non-invasive evaluation of pulmonary glutathione in the exhaled breath condensate of otherwise healthy alcoholics. Respir Med 102:248-55
de Wit, Marjolein; Gennings, Chris; Zilberberg, Marya et al. (2008) Drug withdrawal, cocaine and sedative use disorders increase the need for mechanical ventilation in medical patients. Addiction 103:1500-8
de Wit, Marjolein; Best, Al M; Gennings, Chris et al. (2007) Alcohol use disorders increase the risk for mechanical ventilation in medical patients. Alcohol Clin Exp Res 31:1224-30
Yeh, Mary Y; Burnham, Ellen L; Moss, Marc et al. (2007) Chronic alcoholism alters systemic and pulmonary glutathione redox status. Am J Respir Crit Care Med 176:270-6
Khan, J; Burnham, E L; Moss, M (2006) Acquired weakness in the ICU: critical illness myopathy and polyneuropathy. Minerva Anestesiol 72:401-6
Moss, Marc; Burnham, Ellen Lyda (2006) Alcohol abuse in the critically ill patient. Lancet 368:2231-42

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