In a prospective multi-center clinical study of septic shock patients, alcoholic subjects represented about 50% of the subjects who developed the Acute Respiratory Distress Syndrome (ARDS). The relative risk in alcoholic patients was 3.7 to 1, making it the single most important factor that influenced the development of ARDS. In otherwise healthy alcoholics, the concentration of the critical antioxidant glutathione (GSH) was decreased by 80% suggesting chronic oxidant stress in the alveolar space. In animal models, we have demonstrated that chronic ethanol ingestion results in diverse pulmonary abnormalities including chronic oxidative stress, alveolar-capillary barrier dysfunction, and exaggerated endotoxin-mediated acute lung injury. In the alveolar type II (AT2) cell, chronic ethanol ingestion impairs mitochondrial GSH uptake. This decrease in mitochondrial GSH in the AT2 cell was coupled with decreased mitochondrial membrane integrity, decreased availability of ATP, and increased risk of apoptosis in response to a in vitro or in vivo second hit GSH availability in the mitochondria is key to the ethanol-induced risk of acute lung injury as demonstrated by the capacity of GSH precursors to restore mitochondrial GSH, restore mitochondria integrity, restore AT2 cell function and to decrease the risk of AT2 cell death during endotoxemia. Recent new findings suggest that chronic ethanol promotes endoplasmic reticulum stress and cholesterol loading of the mitochondrial membrane. These effects of ethanol on mitochondrial GSH depletion could be blocked by agents known to inhibit endoplasmic reticulum stress or inhibit cholesterol synthesis. This competitive renewal will examine the novel hypothesis that ethanol-induced endoplasmic reticulum stress in AT2 cells drives mitochondrial GSH depletion and, subsequent mitochondrial stress. Thus, chronic ethanol ingestion upregulates two intrinsic cell death pathways, endoplasmic reticulum stress and mitochondrial stress, that primes the AT2 cell for accelerated apoptosis in response to a second hit.
The aims are as follows: 1) Determine the mechanisms by which chronic ethanol ingestion upregulates two apoptotic pathways in AT2 cells with a particular focus on the role of acetaldehyde as a critical mediator. 2) Determine whether or not ethanol-induced ER stress drives the mitochondrial stress that characterizes the alcoholic AT2 cell. 3) Determine if strategies to relieve ER stress will rescue the alcoholic AT2 cell from its pro-apoptotic phenotype. 4) Determine if relief of ER stress will rescue AT2 cell apoptosis in the alcoholic lung during endotoxemia. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012197-07
Application #
7490451
Study Section
Special Emphasis Panel (ZRG1-RES-B (02))
Program Officer
Orosz, Andras
Project Start
2000-09-01
Project End
2011-06-30
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
7
Fiscal Year
2008
Total Cost
$334,267
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Yeligar, Samantha M; Chen, Michael M; Kovacs, Elizabeth J et al. (2016) Alcohol and lung injury and immunity. Alcohol 55:51-59
Obianyo, Obiamaka; Liang, Yan; Burnham, Ellen L et al. (2015) Metabolic Consequences of Chronic Alcohol Abuse in Non-Smokers: A Pilot Study. PLoS One 10:e0129570
Liang, Yan; Harris, Frank L; Brown, Lou Ann S (2014) Alcohol induced mitochondrial oxidative stress and alveolar macrophage dysfunction. Biomed Res Int 2014:371593
Liang, Yan; Harris, Frank L; Jones, Dean P et al. (2013) Alcohol induces mitochondrial redox imbalance in alveolar macrophages. Free Radic Biol Med 65:1427-1434
Jean, Jyh-Chang; George, Elizabeth; Kaestner, Klaus H et al. (2013) Transcription factor Klf4, induced in the lung by oxygen at birth, regulates perinatal fibroblast and myofibroblast differentiation. PLoS One 8:e54806
Brown, Sheena D; Brown, Lou Ann S (2012) Ethanol (EtOH)-induced TGF-?1 and reactive oxygen species production are necessary for EtOH-induced alveolar macrophage dysfunction and induction of alternative activation. Alcohol Clin Exp Res 36:1952-62
Tang, Sonja M; Gabelaia, Levan; Gauthier, Theresa W et al. (2009) N-acetylcysteine improves group B streptococcus clearance in a rat model of chronic ethanol ingestion. Alcohol Clin Exp Res 33:1197-201
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, Sheena D; Gauthier, Theresa W; Brown, Lou Ann S (2009) Impaired terminal differentiation of pulmonary macrophages in a Guinea pig model of chronic ethanol ingestion. Alcohol Clin Exp Res 33:1782-93
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

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