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. Despite modern neonatal intensive care, chronic lung injury in the premature newborn, known as bronchopulmonary dysplasia (BPD) causes significant morbidity and mortality. Late onset sepsis (LOS) in the premature newborn is linked to the development of BPD. The hypothesized shift in the signaling balance between excessive transforming growth factor-beta 1 (TGFpl) and diminished granulocyte macrophage-colony stimulating factor (GM-CSF) in the """"""""alcoholic lung"""""""" at risk for adult respiratory distress syndrome and infection is a central theme to investigations within the Emory Alcohol and Lung Biology Center. The risk of lung injury for the newborn, particularly the premature newborn, exposed to alcohol in utero has received little attention. We have compelling evidence from pre-clinical animal models and clinical human studies that in utero alcohol exposure increased oxidant stress in the neonatal lung, increased TGFpl and decreased GM-CSF in the developing airway. We have demonstrated dysfunction of the fetal alcohol-exposed animal alveolar macrophage while human clinical data suggested an increased the risk of BPD and sepsis for the alcohol-exposed premature newborn. We hypothesize that increased pulmonary oxidant stress in the premature newborn exposed to alcohol in utero shifts the signaling balance towards excessive TGFj3i and diminished GM-CSF, resulting in AM dysfunction and an increased risk of BPD and LOS. We will extend this hypothesis to the clinical arena of the neonatal intensive care unit in this new Project within the Emory Alcohol and Lung Biology Center. Within our unique network of researchers, we have the novel opportunity to address these vitally important and as of yet unanswered questions for the human premature newborn. With the expertise of the Clinical Core, we will prospectively identify the alcohol-exposed premature newborn and evaluate fatty acid ethyl esters as a potential biomarker of prenatal alcohol exposure. Interactions with Center investigators will catalyze translational studies identifying biochemical biomarkers of this exposure in the premature lung, determining alcohol's effect on premature human alveolar macrophage, and ultimately defining the risks of bronchopulmonary dysplasia and late onset sepsis in the alcohol-exposed premature newborn infant. These studies will provide a firm foundation for future investigations aimed at the development of potential therapeutic interventions for our tiniest at-risk patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA013757-10
Application #
8426098
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
$69,996
Indirect Cost
$15,777
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 :

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