Skip to main content
SpringerLink
Log in

Alcohol-Mediated Oxidative Stress in the Airway: The Unique Role of Thiol Depletion

  • Chapter
  • First Online:
Alcohol Use Disorders and the Lung

Part of the book series: Respiratory Medicine ((RM,volume 14))

Abstract

Individuals with alcohol use disorders (AUDs) have increased susceptibility to developing respiratory infections and the Acute Respiratory Distress Syndrome (ARDS). Oxidative stress is a primary contributor to the pathogenesis of these alcohol-related derangements. Sources of alcohol-induced lung oxidative stress include depletion of cytosolic and mitochondrial glutathione (GSH), increases in reactive oxygen species (ROS) and reactive nitrogen species (RNS), and enhanced expression and activity of NADPH oxidases (Nox). Alcohol-mediated oxidative stress in the lung leads to tissue injury and barrier dysfunction, phospholipid peroxidation and DNA oxidation, fibronectin production, apoptosis, and dysregulation of cellular zinc transport and immune function. Since these consequences directly relate to rising healthcare costs and associated hospitalizations of alcoholic patients, therapeutic interventions to attenuate alcohol-induced pulmonary oxidative stress are critical. Treatments recently under investigation in preclinical studies and, in some cases clinical studies, include drugs that activate peroxisome proliferator-activated receptor gamma (PPARγ), dietary zinc supplementation, and treatment with GSH precursors. These interventions are designed to attenuate alcohol-mediated increases in lung oxidative stress with the goal of restoring healthy lung function and thereby decreasing the risk of lung infections and injury in this vulnerable population.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 59.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 79.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AUD:

Alcohol use disorder

ARDS:

Acute respiratory distress syndrome

GSH:

Glutathione

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

Nox:

NADPH oxidases

PPARγ:

Peroxisome proliferator-activated receptor gamma

•O2 − :

Superoxide

H2O2 :

Hydrogen peroxide

•OH:

Hydroxyl radical

•NO:

Nitric oxide

ONOO-:

Peroxynitrite

ELF:

Epithelial lining fluid

GSSG:

Glutathione disulfide

BAL:

Bronchoalveolar lavage

TGFβ1:

Transforming growth factor beta 1

SA:

Small aggregate

LA:

Large aggregate

MMP:

Matrix metalloproteinase

TNFα:

Tumor-necrosis factor alpha

GM-CSF:

Granulocyte/macrophage colony-stimulating factor

ARE:

Antioxidant response element

SAMe:

S-Adenosyl-methionine

NAC:

N-Acetylcysteine

GBS:

Group B Streptococcus pneumoniae

References

  1. Erickson SE, Martin GS, Davis JL, Matthay MA, Eisner MD, Network NNA. Recent trends in acute lung injury mortality: 1996-2005. Crit Care Med. 2009;37(5):1574–9.

    Article  PubMed  Google Scholar 

  2. Brown LA, Harris FL, Ping XD, Gauthier TW. Chronic ethanol ingestion and the risk of acute lung injury: a role for glutathione availability? Alcohol. 2004;33(3):191–7.

    Article  PubMed  CAS  Google Scholar 

  3. Manautou JE, Buss NJ, Carlson GP. Oxidative and non-oxidative metabolism of ethanol by the rabbit lung. Toxicol Lett. 1992;62(1):93–9.

    Article  PubMed  CAS  Google Scholar 

  4. Lieber CS. Biochemical factors in alcoholic liver disease. Semin Liver Dis. 1993;13(2): 136–53.

    Article  PubMed  CAS  Google Scholar 

  5. Pacht ER, Timerman AP, Lykens MG, Merola AJ. Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome. Chest. 1991;100(5): 1397–403.

    Article  PubMed  CAS  Google Scholar 

  6. Bunnell E, Pacht ER. Oxidized glutathione is increased in the alveolar fluid of patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1993;148(5):1174–8.

    Article  PubMed  CAS  Google Scholar 

  7. Moss M, Guidot DM, Wong-Lambertina M, Ten Hoor T, Perez RL, Brown LA. The effects of chronic alcohol abuse on pulmonary glutathione homeostasis. Am J Respir Crit Care Med. 2000;161(2 Pt 1):414–9.

    Article  PubMed  CAS  Google Scholar 

  8. Holguin F, Moss I, Brown LA, Guidot DM. Chronic ethanol ingestion impairs alveolar type II cell glutathione homeostasis and function and predisposes to endotoxin-mediated acute edematous lung injury in rats. J Clin Invest. 1998;101(4):761–8.

    Article  PubMed  CAS  Google Scholar 

  9. Guidot DM, Modelska K, Lois M, Jain L, Moss IM, Pittet JF, et al. Ethanol ingestion via glutathione depletion impairs alveolar epithelial barrier function in rats. Am J Physiol Lung Cell Mol Physiol. 2000;279(1):L127–35.

    PubMed  CAS  Google Scholar 

  10. Brown LA, Harris FL, Guidot DM. Chronic ethanol ingestion potentiates TNF-alpha-mediated oxidative stress and apoptosis in rat type II cells. Am J Physiol Lung Cell Mol Physiol. 2001;281(2):L377–86.

    PubMed  CAS  Google Scholar 

  11. Brown LA, Harris FL, Bechara R, Guidot DM. Effect of chronic ethanol ingestion on alveolar type II cell: glutathione and inflammatory mediator-induced apoptosis. Alcohol Clin Exp Res. 2001;25(7):1078–85.

    Article  PubMed  CAS  Google Scholar 

  12. Polikandriotis JA, Rupnow HL, Brown LA, Hart CM. Chronic ethanol ingestion increases nitric oxide production in the lung. Alcohol. 2007;41(5):309–16.

    Article  PubMed  CAS  Google Scholar 

  13. Polikandriotis JA, Rupnow HL, Hart CM. Chronic ethanol exposure stimulates endothelial cell nitric oxide production through PI-3 kinase-and hsp90-dependent mechanisms. Alcohol Clin Exp Res. 2005;29(11):1932–8.

    Article  PubMed  CAS  Google Scholar 

  14. Wagner MC, Yeligar SM, Brown LA, Michael HC. PPARgamma ligands regulate NADPH oxidase, eNOS, and barrier function in the lung following chronic alcohol ingestion. Alcohol Clin Exp Res. 2012;36(2):197–206.

    Article  PubMed  CAS  Google Scholar 

  15. Brown DI, Griendling KK. Nox proteins in signal transduction. Free Rad Biol Med. 2009;47(9):1239–53.

    Article  PubMed  CAS  Google Scholar 

  16. Mittal M, Roth M, Konig P, Hofmann S, Dony E, Goyal P, et al. Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res. 2007;101(3):258–67.

    Article  PubMed  CAS  Google Scholar 

  17. Goyal P, Weissmann N, Grimminger F, Hegel C, Bader L, Rose F, et al. Upregulation of NAD(P)H oxidase 1 in hypoxia activates hypoxia-inducible factor 1 via increase in reactive oxygen species. Free Rad Biol Med. 2004;36(10):1279–88.

    Article  PubMed  CAS  Google Scholar 

  18. Polikandriotis JA, Rupnow HL, Elms SC, Clempus RE, Campbell DJ, Sutliff RL, et al. Chronic ethanol ingestion increases superoxide production and NADPH oxidase expression in the lung. Am J Res Cell Mol Biol. 2006;34(3):314–9.

    Article  CAS  Google Scholar 

  19. Yeligar SM, Harris FL, Hart CM, Brown LA. Ethanol induces oxidative stress in alveolar macrophages via upregulation of NADPH oxidases. J Immunol. 2012;188(8):3648–57.

    Article  PubMed  CAS  Google Scholar 

  20. Dong J, Sulik KK, Chen SY. The role of NOX enzymes in ethanol-induced oxidative stress and apoptosis in mouse embryos. Toxicol Lett. 2010;193(1):94–100.

    Article  PubMed  CAS  Google Scholar 

  21. Guidot DM, Hart CM. Alcohol abuse and acute lung injury: epidemiology and pathophysiology of a recently recognized association. J Invest Med. 2005;53(5):235–45.

    Article  Google Scholar 

  22. Velasquez A, Bechara RI, Lewis JF, Malloy J, McCaig L, Brown LA, et al. Glutathione replacement preserves the functional surfactant phospholipid pool size and decreases sepsis-mediated lung dysfunction in ethanol-fed rats. Alcohol Clin Exp Res. 2002; 26(8):1245–51.

    Article  PubMed  CAS  Google Scholar 

  23. Moss M, Bucher B, Moore FA, Moore EE, Parsons PE. The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA. 1996;275(1):50–4.

    Article  PubMed  CAS  Google Scholar 

  24. Moss M, Parsons PE, Steinberg KP, Hudson LD, Guidot DM, Burnham EL, et al. Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock. Crit Care Med. 2003;31(3):869–77.

    Article  PubMed  Google Scholar 

  25. Bechara RI, Pelaez A, Palacio A, Joshi PC, Hart CM, Brown LA, et al. Angiotensin II mediates glutathione depletion, transforming growth factor-beta1 expression, and epithelial barrier dysfunction in the alcoholic rat lung. Am J Physiol Lung Cell Mol Physiol. 2005;289(3):L363–70.

    Article  PubMed  CAS  Google Scholar 

  26. Burnham EL, Moss M, Harris F, Brown LA. Elevated plasma and lung endothelial selectin levels in patients with acute respiratory distress syndrome and a history of chronic alcohol abuse. Crit Care Med. 2004;32(3):675–9.

    Article  PubMed  CAS  Google Scholar 

  27. Guidot DM, Brown LA. Mitochondrial glutathione replacement restores surfactant synthesis and secretion in alveolar epithelial cells of ethanol-fed rats. Alcohol Clin Exp Res. 2000; 24(7):1070–6.

    Article  PubMed  CAS  Google Scholar 

  28. Kim H, Oh E, Im H, Mun J, Yang M, Khim JY, et al. Oxidative damages in the DNA, lipids, and proteins of rats exposed to isofluranes and alcohols. Toxicology. 2006;220(2–3):169–78.

    Article  PubMed  CAS  Google Scholar 

  29. Burnham EL, Moss M, Ritzenthaler JD, Roman J. Increased fibronectin expression in lung in the setting of chronic alcohol abuse. Alcohol Clin Exp Res. 2007;31(4):675–83.

    PubMed  CAS  Google Scholar 

  30. Brown LA, Ritzenthaler JD, Guidot DM, Roman J. Alveolar type II cells from ethanol-fed rats produce a fibronectin-enriched extracellular matrix that promotes monocyte activation. Alcohol. 2007;41(5):317–24.

    Article  PubMed  CAS  Google Scholar 

  31. Boe DM, Nelson S, Zhang P, Quinton L, Bagby GJ. Alcohol-induced suppression of lung chemokine production and the host defense response to Streptococcus pneumoniae. Alcohol Clin Exp Res. 2003;27(11):1838–45.

    Article  PubMed  CAS  Google Scholar 

  32. Trapnell BC, Whitsett JA. Gm-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu Rev Physiol. 2002;64:775–802.

    Article  PubMed  CAS  Google Scholar 

  33. Joshi PC, Mehta A, Jabber WS, Fan X, Guidot DM. Zinc deficiency mediates alcohol-induced alveolar epithelial and macrophage dysfunction in rats. Am J Res Cell Mol Biol. 2009;41(2): 207–16.

    Article  CAS  Google Scholar 

  34. Brown SD, Brown LA. Ethanol (EtOH)-induced TGF-beta(1) and reactive oxygen species production are necessary for EtOH-induced alveolar macrophage dysfunction and induction of alternative activation. Alcohol Clin Exp Res. 2012;36(11):1952–62.

    Article  PubMed  CAS  Google Scholar 

  35. Mehta AJ, Joshi PC, Fan X, Brown LA, Ritzenthaler JD, Roman J, et al. Zinc supplementation restores PU.1 and Nrf2 nuclear binding in alveolar macrophages and improves redox balance and bacterial clearance in the lungs of alcohol-fed rats. Alcohol Clin Exp Res. 2011;35(8):1519–28.

    PubMed  CAS  Google Scholar 

  36. Hwang J, Kleinhenz DJ, Lassegue B, Griendling KK, Dikalov S, Hart CM. Peroxisome proliferator-activated receptor-gamma ligands regulate endothelial membrane superoxide production. Am J Physiol Cell Physiol. 2005;288(4):C899–905.

    Article  PubMed  CAS  Google Scholar 

  37. Hwang J, Kleinhenz DJ, Rupnow HL, Campbell AG, Thule PM, Sutliff RL, et al. The PPARgamma ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice. Vasc Pharmacol. 2007;46(6):456–62.

    Article  CAS  Google Scholar 

  38. Nisbet RE, Bland JM, Kleinhenz DJ, Mitchell PO, Walp ER, Sutliff RL, et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Res Cell Mol Biol. 2010;42(4):482–90.

    Article  Google Scholar 

  39. McClain CJ, Antonow DR, Cohen DA, Shedlofsky SI. Zinc metabolism in alcoholic liver disease. Alcohol Clin Exp Res. 1986;10(6):582–9.

    Article  PubMed  CAS  Google Scholar 

  40. Kang X, Zhong W, Liu J, Song Z, McClain CJ, Kang YJ, et al. Zinc supplementation reverses alcohol-induced steatosis in mice through reactivating hepatocyte nuclear factor-4alpha and peroxisome proliferator-activated receptor-alpha. Hepatology. 2009;50(4):1241–50.

    Article  PubMed  CAS  Google Scholar 

  41. Tudor R, Zalewski PD, Ratnaike RN. Zinc in health and chronic disease. J Nutri Health Aging. 2005;9(1):45–51.

    CAS  Google Scholar 

  42. Mehta AJ, Guidot DM. Alcohol abuse, the alveolar macrophage and pneumonia. Am J Med Sci. 2012;343(3):244–7.

    Article  PubMed  Google Scholar 

  43. Brown LA, Ping XD, Harris FL, Gauthier TW. Glutathione availability modulates alveolar macrophage function in the chronic ethanol-fed rat. Am J Physiol Lung Cell Mol Physiol. 2007;292(4):L824–32.

    Article  PubMed  CAS  Google Scholar 

  44. Gauthier TW, Ping XD, Harris FL, Wong M, Elbahesh H, Brown LA. Fetal alcohol exposure impairs alveolar macrophage function via decreased glutathione availability. Pediatr Res. 2005;57(1):76–81.

    Article  PubMed  CAS  Google Scholar 

  45. Tang SM, Gabelaia L, Gauthier TW, Brown LA. N-acetylcysteine improves group B streptococcus clearance in a rat model of chronic ethanol ingestion. Alcohol Clin Exp Res. 2009;33(7): 1197–201.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory University, 2015 Uppergate Drive, Atlanta, GA, 30322, USA

    Samantha M. Yeligar M.S., Ph.D. & Yan Liang Ph.D.

  2. Children’s Healthcare of Atlanta Center for Developmental Lung Biology, Atlanta, GA, USA

    Samantha M. Yeligar M.S., Ph.D. & Yan Liang Ph.D.

  3. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory University Emory + Children’s Healthcare of Atlanta Center for Developmental Lung Biology, Atlanta, GA, USA

    Lou Ann S. Brown Ph.D.

Authors
  1. Samantha M. Yeligar M.S., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan Liang Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lou Ann S. Brown Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine and the Atlanta VA Medical Center, Atlanta, Georgia, USA

    David M. Guidot

  2. Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine and the Atlanta VA Medical Center, Decatur, Georgia, USA

    Ashish J. Mehta

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Yeligar, S.M., Liang, Y., Brown, L.A.S. (2014). Alcohol-Mediated Oxidative Stress in the Airway: The Unique Role of Thiol Depletion. In: Guidot, D., Mehta, A. (eds) Alcohol Use Disorders and the Lung. Respiratory Medicine, vol 14. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-8833-0_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-8833-0_9

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4614-8832-3

  • Online ISBN: 978-1-4614-8833-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation