The fundamental and unifying hypothesis in the Emory Alcohol and Lung Biology Center competitive renewal is that chronic alcohol abuse causes oxidant stress and disrupts normal regulatory pathways, thereby producing an """"""""alcoholic lung phenotype"""""""" that is highly susceptible to respiratory infections, acute lung injury, and other serious lung diseases. Disruption of the alveolar epithelial barrier is a cardinal feature of serious lung injuries from insults such as infection, trauma, pancreatitis, and gastric aspiration;any of these insults can cause the acute respiratory distress syndrome (ARDS), a devastating form of acute lung injury with a mortality of 40-60%. Importantly, investigators in the Emory Alcohol and Lung Biology Center have determined that alcohol abuse independently increases the risk of ARDS ~4-fold. The alveolar epithelial barrier consists of at least three important components: alveolar type I (AT1) cells, alveolar type 2 (AT2) cells, and the tight junctions that bind these cells together. All three components are regulated and contribute to normal barrier function. In this competitive renewal the project investigators will capitalize on the novel discoveries made in the previous cycle and will define the precise molecular mechanisms by which the alveolar epithelial barrier is impaired in the alcoholic lung. The studies in the previous cycle and new preliminary findings presented in this renewal application reveal that two key signal transduction pathways, mediated by granulocyte/macrophage colony-stimulating factor (GM-CSF) and transforming growth factor B1 (TGFB1), have antagonistic effects on the alveolar epithelium: GM-CSF promotes barrier integrity whereas TGFB1 induces barrier disruption. In Project 1, the investigators hypothesize that alcohol-induced oxidant stress, and the consequent shift in the signaling balance between GM-CSF and TGFB1, destabilizes alveolar epithelial tight junctions and renders the alcoholic lung more vulnerable to acute edematous injury. The investigators in this project will use their established animal model of chronic alcohol ingestion in rats to determine the discrete mechanisms by which this imbalance in GM-CSF and TGFB1, signaling alters the normally tight alveolar epithelial barrier chronically, as well as how this imbalance is exacerbated and contributes to acute edematous injury in response to sepsis and other inflammatory insults. Further, they will translate these studies to the clinical setting through direct collaborations with the Clinical Core. The proposed studies have enromous implications for our understanding of the mechanisms by which alcohol abuse renders otherwise healthy individuals at high risk for ARDS, as well as our ability to design and test novel therapeutic interventions.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Specialized Center (P50)
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Special Emphasis Panel (ZAA1)
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Emory University
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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
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
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
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
Alford, Lea M; Stoddard, Daniel; Li, Jennifer H et al. (2016) The nexin link and B-tubule glutamylation maintain the alignment of outer doublets in the ciliary axoneme. Cytoskeleton (Hoboken) 73:331-40
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
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
Yeligar, Samantha M; Chen, Michael M; Kovacs, Elizabeth J et al. (2016) Alcohol and lung injury and immunity. Alcohol 55:51-59
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

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