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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA013757-10
Application #
8426094
Study Section
Special Emphasis Panel (ZAA1-BB)
Project Start
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
10
Fiscal Year
2013
Total Cost
$228,583
Indirect Cost
$51,524
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
Gauthier, Theresa W; Brown, Lou Ann S (2016) In utero alcohol effects on foetal, neonatal and childhood lung disease. Paediatr Respir Rev :
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
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
Yeligar, Samantha M; Mehta, Ashish J; Harris, Frank L et al. (2016) Peroxisome Proliferator-Activated Receptor γ Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction. Am J Respir Cell Mol Biol 55:35-46
Sueblinvong, Viranuj; Mills, Stephen T; Neujahr, David C et al. (2016) Nuclear Thioredoxin-1 Overexpression Attenuates Alcohol-Mediated Nrf2 Signaling and Lung Fibrosis. Alcohol Clin Exp Res 40:1846-56
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
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
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
Klingensmith, Nathan J; Yoseph, Benyam P; Liang, Zhe et al. (2016) Epidermal Growth Factor Improves Intestinal Integrity and Survival in Murine Sepsis Following Chronic Alcohol Ingestion. Shock :

Showing the most recent 10 out of 101 publications