Acute Respiratory Distress Syndrome (ARDS) is a common and severe form of acute lung injury that is associated with mortality of approximately 50 percent. A prospective study of 351 critically ill patients recently identified a history of chronic alcohol abuse with an increased incidence and severity of ARDS, regardless of the at-risk diagnosis. This observation identifies chronic alcohol abuse as the first reported comorbid variable that significantly increases the patient's risk of developing ARDS. Glutathione (GSH) is an essential component of the pulmonary antioxidant system and decreased GSH in the epithelial lining fluid has been associated with ARDS. Studies in the investigator's laboratory demonstrated that alcoholic adults without cirrhosis have and 80 percent decrease in GSH in the epithelial lining fluid, possibly due to decreased GSH availability from plasma. In a rat model of chronic ethanol ingestion, decreased GSH in the epithelial lining fluid and alveolar type II cells was associated with increased susceptibility to sepis-mediated acute lung injury. The mechanisms by which ethanol-induced GSH depletion increases susceptibility to acute lung injury is the focus of this application. One hallmark of ARDS is altered alveolar matrix homeostasis as characterized by excessive alveolar matrix deposition and matrix turnover. Studies in the investigator's laboratory have demonstrated that in the rat model, ethanol-induced GSH depletion was associated with alveolar type II cells that produce an altered, unstable extracellular matrix that was unable to support type II cell functions. When sepsis was superimposed on ethanol ingestion, the lavage fluid had greater gelatinase activity. Prevention of many of these altered parameters with GSH precursors indicates the central role of GSH depletion in the process. This lead to the following hypothesis: chronic ethanol ingestion predisposes to acute lung injury by decreasing alveolar GSH which subsequently alters the homeostasis of the alveolar epithelial extracellular matrix. In the first three aims, the investigators will use the rat model of chronic ethanol ingestion to determine if ethanol predisposes to acute lung injury via altered matrix homeostasis (Aim1), if sepsis potentiates the ethanol-induced effects on matrix homeostasis (Aim 2) and if GSH availability mediates these effects on matrix homeostasis (Aim3).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067399-02
Application #
6390991
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Harabin, Andrea L
Project Start
2000-09-30
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$228,000
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Tian, Junqiang; Brown, Lou Ann S; Jones, Dean P et al. (2009) Intestinal redox status of major intracellular thiols in a rat model of chronic alcohol consumption. JPEN J Parenter Enteral Nutr 33:662-8
Brown, Lou Ann S; Ping, Xiao-Du; Harris, Frank L et al. (2007) Glutathione availability modulates alveolar macrophage function in the chronic ethanol-fed rat. Am J Physiol Lung Cell Mol Physiol 292:L824-32
Brown, Lou Ann S; Harris, Frank L; Ping, Xiao-Du et al. (2004) Chronic ethanol ingestion and the risk of acute lung injury: a role for glutathione availability? Alcohol 33:191-7