Alcohol abuse directly affects 15-30 million Americans and is a major risk factor for several devastating lung diseases including pneumonia. Experimentally, alcohol ingestion causes oxidant stress within the alveolar space and severely compromises alveolar macrophage immune function by dampening GM-CSF signaling and priming of these cells. Clinical studies have verified that chronic alcohol abuse, even in otherwise healthy humans, causes severe oxidant stress and alveolar macrophage dysfunction that parallel the experimental models. Although it has long been recognized that alcohol abuse is associated with zinc deficiency, and that zinc deficiency is particularly damaging to immune cell functions, the role of zinc bioavailability in mediating the alcoholic lung phenotype has not been investigated. Preliminary and published data in this application implicate zinc deficiency in the previously observed defects in GM-CSF signaling to the alveolar macrophage through its master transcription factor, PU.1, but also reveal new evidence that zinc deficiency suppresses activation of the antioxidant response element by inhibiting expression of its master transcription factor, Nrf2. To unify these findings into a single pathophysiological scheme, we hypothesize that alcohol inhibits zinc transport by the alveolar epithelium into the alveolar space, and that the consequent zinc deficiency within the alveolar macrophage impairs both GM-CSF signaling and activation of the antioxidant response element by coordinately interfering with their master transcription factors. Further, we hypothesize that zinc supplementation can mitigate if not reverse the alveolar macrophage dysfunction that causes so much morbidity and mortality in these vulnerable individuals. This research proposal includes three integrated aims that test the overarching hypothesis;specifically, that chronic alcohol ingestion impairs zinc transport across the alveolar epithelium into the alveolar space (Aim 1), which leads to zinc deficiency within the alveolar macrophage that interferes with critical signaling through the antioxidant response element and GM-CSF (Aim 2), and that dietary zinc supplementation can prevent and/or reverse the alcoholic macrophage phenotype in the long-term, whereas GM-CSF and/or thiol antioxidants can rescue the alcoholic macrophage in the acute setting (Aim 3). This project has important implications not only for our understanding of the fundamental mechanisms by which alcohol abuse renders the lung susceptible to a range of acute illnesses, but also for our ability to identify and test novel therapeutic strategies in clinical trials targeted to this highly vulnerable population. Further, the results of this project could change our recommendations for treatment of chronic alcohol abuse;specifically, dietary zinc supplementation could potentially prevent the development of alcohol- mediated susceptibility to lung diseases (and perhaps protect other target organs as well), and thereby prevent or at least limit alcohol-related organ damage while these individuals undergo chronic treatment for their alcohol use disorders.

Public Health Relevance

Alcohol abuse causes many health problems. In particular, even otherwise healthy individuals who consume excessive amounts of alcohol are susceptible to serious lung infections and other causes of respiratory failure, leading to tens of thousands of death in the U.S. alone each year. This project is designed to test the hypothesis that deficiency of the important nutrient zinc is a primary cause of alcohol-related lung injury, and that dietary zinc supplementation could prove to be an effective means of improving lung health in the 15-30 million Americans who suffer from alcohol abuse or dependence.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Jung, Kathy
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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Staitieh, Bashar S; Egea, Eduardo E; Fan, Xian et al. (2018) Chronic Alcohol Ingestion Impairs Rat Alveolar Macrophage Phagocytosis via Disruption of RAGE Signaling. Am J Med Sci 355:497-505
Mehta, Ashish J; Guidot, David M (2017) Alcohol and the Lung. Alcohol Res 38:243-254
Staitieh, Bashar S; Ding, Lingmei; Neveu, Wendy A et al. (2017) HIV-1 decreases Nrf2/ARE activity and phagocytic function in alveolar macrophages. J Leukoc Biol 102:517-525
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
Staitieh, Bashar S; Egea, Eduardo E; Fan, Xian et al. (2015) Activation of Alveolar Macrophages with Interferon-? Promotes Antioxidant Defenses via the Nrf2-ARE Pathway. J Clin Cell Immunol 6:
Overgaard, Christian E; Schlingmann, Barbara; Dorsainvil White, StevenClaude et al. (2015) The relative balance of GM-CSF and TGF-?1 regulates lung epithelial barrier function. Am J Physiol Lung Cell Mol Physiol 308:L1212-23
Staitieh, Bashar S; Fan, Xian; Neveu, Wendy et al. (2015) Nrf2 regulates PU.1 expression and activity in the alveolar macrophage. Am J Physiol Lung Cell Mol Physiol 308:L1086-93
Staitieh, Bashar; Guidot, David M (2014) Noninfectious pulmonary complications of human immunodeficiency virus infection. Am J Med Sci 348:502-11
Sueblinvong, Viranuj; Kerchberger, Vern E; Saghafi, Ramin et al. (2014) Chronic alcohol ingestion primes the lung for bleomycin-induced fibrosis in mice. Alcohol Clin Exp Res 38:336-43
Sueblinvong, Viranuj; Tseng, Victor; Smith, Tierra et al. (2014) TGF?1 mediates alcohol-induced Nrf2 suppression in lung fibroblasts. Alcohol Clin Exp Res 38:2731-42

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