Investigators in this Center Application have identified chronic alcohol abuse as a co-morbid variable that significantly increases the incidence and severity of the Acute Respiratory Distress Syndrome (ARDS). The overall theme of this Center application postulates that chronic ethanol ingestion enhances the risk of alveolar flooding in response to inflammatory mediators and activated neutrophils. This suggests a """"""""two-hit"""""""" model wherein chronic ethanol ingestion constitutes the first hit but does not generate pulmonary dysfunction. However, the first hit does predispose the lung to an enhanced response to the inflammatory mediators and activated neutrophils produced during sepsis. We postulate that one mechanism by which chronic ethanol ingestion predisposes the lung to endothelial barrier dysfunction involves ethanol-induced decreases in the availability of the antioxidant glutathione (GSH), particularly the mitochondrial pool in pulmonary microvascular endothelial cells (MVEC). When GSH availability decreases, the reactive oxygen species (ROS) generated during normal respiration and ethanol detoxification becomes amplified. With chronic exposure to ROS, the MVEC is altered and the basal expression of adhesion molecules are upregulated. During sepsis, the adhesion of the activated neutrophils and the microenvironment is potentiated. The ethanol-induced GSH depletion then amplifies the ROS produced resulting in mitochondrial dysfunction and decreased ATP generation. With limited ATP availability, the MVEC are more susceptible to cytotoxin- and neutrophil-induced apoptosis and necrosis. When MVEC death is enhanced, barrier dysfunction and neutrophil migration is potentiated. Furthermore, we propose that GSH precursors will attenuate this enhanced endothelial:neutrophil interaction and result in decreased sepsis-induced acute lung injury. Using a rat model of chronic ethanol ingestion, three Specific Aims will explore this hypothesis to determine: 1) if chronic ethanol ingestion potentiates inflammatory mediator-induced oxidative stress in MVEC, 2) if ethanol-induced chronic ROS up regulates MVEC adhesion factor expression and neutrophil transmigration during sepsis and 3) if intervention with GSH precursors will attenuate ethanol potentiation of adhesion factor expression and neutrophil transmigration during sepsis. This proposal will improve our understanding of the relationship between alcohol and lung injury and potentially identify strategies for ARDS prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA013757-05
Application #
7557258
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
5
Fiscal Year
2007
Total Cost
$237,353
Indirect Cost
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Gross, Teresa S; Harris, Frank; Brown, Lou Ann S et al. (2017) Ethyl linolenate is elevated in meconium of very-low-birth-weight neonates exposed to alcohol in utero. Pediatr Res 81:461-467
Cornely, Ronald M; Schlingmann, Barbara; Shepherd, Whitney S et al. (2017) Two common human CLDN5 alleles encode different open reading frames but produce one protein isoform. Ann N Y Acad Sci 1397:119-129
Klingensmith, Nathan J; Yoseph, Benyam P; Liang, Zhe et al. (2017) Epidermal Growth Factor Improves Intestinal Integrity and Survival in Murine Sepsis Following Chronic Alcohol Ingestion. Shock 47:184-192
Gauthier, Theresa W; Brown, Lou Ann S (2017) In utero alcohol effects on foetal, neonatal and childhood lung disease. Paediatr Respir Rev 21:34-37
Kempker, Jordan A; Magee, Matthew J; Cegielski, J Peter et al. (2016) Associations Between Vitamin D Level and Hospitalizations With and Without an Infection in a National Cohort of Medicare Beneficiaries. Am J Epidemiol 183:920-9
Margoles, Lindsay M; Mittal, Rohit; Klingensmith, Nathan J et al. (2016) Chronic Alcohol Ingestion Delays T Cell Activation and Effector Function in Sepsis. PLoS One 11:e0165886
Schlingmann, Barbara; Overgaard, Christian E; Molina, Samuel A et al. (2016) Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions. Nat Commun 7:12276
Yeligar, Samantha M; Chen, Michael M; Kovacs, Elizabeth J et al. (2016) Alcohol and lung injury and immunity. Alcohol 55:51-59
Gauthier, Theresa W; Guidot, David M; Kelleman, Michael S et al. (2016) Maternal Alcohol Use During Pregnancy and Associated Morbidities in Very Low Birth Weight Newborns. Am J Med Sci 352:368-375
Cochi, Shea E; Kempker, Jordan A; Annangi, Srinadh et al. (2016) Mortality Trends of Acute Respiratory Distress Syndrome in the United States from 1999 to 2013. Ann Am Thorac Soc 13:1742-1751

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