Oxidative Stress in Chronic Obstructive Pulmonary Disease

  • Mariana A. Antunes
  • Fernanda F. Cruz
  • Patricia R. M. Rocco


Chronic obstructive pulmonary disease (COPD), which comprises chronic bronchitis and emphysema phenotypes, is characterized by airflow obstruction and pulmonary inflammation and tissue disruption. It is also associated with several extrapulmonary manifestations and frequently occurs simultaneously with other disorders that have an additive influence on patients’ quality of life. COPD is usually a disease of aging, and the main risk factor for its development is smoking. A particularly remarkable etiologic factor that drives COPD pathogenesis is oxidative and carbonyl stress which originates in the pulmonary milieu after prolonged exposure to cigarette smoke or to the by-products of combustion of biomass fuels. The fact that COPD progresses even after smoking cessation is probably attributable to numerous exogenous and, especially, endogenous sources of reactive oxygen species (ROS), although this involvement has yet to be proven. The function of key cells, as well as the levels of significant oxidant and antioxidant molecules, may be dysregulated in COPD. Oxidative stress has been related to increased expression of proinflammatory genes, inability to resolve inflammation, insensitivity to corticosteroids, impairment of endogenous antioxidant defenses, accelerated lung senescence, and elevated risk of developing emphysema.


  1. Agler AH, Kurth T, Gaziano JM, Buring JE, Cassano PA (2011) Randomised vitamin E supplementation and risk of chronic lung disease in the women’s health study. Thorax 66(4):320–325CrossRefGoogle Scholar
  2. Aldonyte R, Jansson L, Piitulainen E, Janciauskiene S (2003) Circulating monocytes from healthy individuals and COPD patients. Respir Res 4:11CrossRefGoogle Scholar
  3. Barnes PJ (2000) Chronic obstructive pulmonary disease. N Engl J Med 343(4):269–280CrossRefGoogle Scholar
  4. Barreiro E, Peinado VI, Galdiz JB, Ferrer E, Marin-Corral J, Sanchez F et al (2010) Cigarette smoke-induced oxidative stress: a role in chronic obstructive pulmonary disease skeletal muscle dysfunction. Am J Respir Crit Care Med 182(4):477–488CrossRefGoogle Scholar
  5. Bialas AJ, Sitarek P, Milkowska-Dymanowska J, Piotrowski WJ, Gorski P (2016) The role of mitochondria and oxidative/antioxidative imbalance in pathobiology of chronic obstructive pulmonary disease. Oxidative Med Cell Longev 2016:7808576CrossRefGoogle Scholar
  6. Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134(3):707–716CrossRefGoogle Scholar
  7. Breitzig M, Bhimineni C, Lockey R, Kolliputi N (2016) 4-Hydroxy-2-nonenal: a critical target in oxidative stress? Am J Physiol Cell Physiol 311(4):C537–CC43CrossRefGoogle Scholar
  8. Canbaz D, Logiantara A, Hamers T, van Ree R, van Rijt LS (2016) Indoor pollutant Hexabromocyclododecane has a modest immunomodulatory effect on house dust mite induced allergic asthma in mice. Environ Sci Technol 50(1):405–411CrossRefGoogle Scholar
  9. Carp H, Miller F, Hoidal JR, Janoff A (1982) Potential mechanism of emphysema: alpha 1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity. Proc Natl Acad Sci U S A 79(6):2041–2045CrossRefGoogle Scholar
  10. Chan DC (2006) Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 22:79–99CrossRefGoogle Scholar
  11. Cloonan SM, Mumby S, Adcock IM, Choi AMK, Chung KF, Quinlan GJ (2017) The “Iron”-y of iron overload and iron deficiency in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 196(9):1103–1112CrossRefGoogle Scholar
  12. Conti V, Corbi G, Manzo V, Pelaia G, Filippelli A, Vatrella A (2015) Sirtuin 1 and aging theory for chronic obstructive pulmonary disease. Anal Cell Pathol 2015:897327CrossRefGoogle Scholar
  13. de Batlle J, Barreiro E, Romieu I, Mendez M, Gomez FP, Balcells E et al (2010) Dietary modulation of oxidative stress in chronic obstructive pulmonary disease patients. Free Radic Res 44(11):1296–1303CrossRefGoogle Scholar
  14. Decramer M, Janssens W, Miravitlles M (2012) Chronic obstructive pulmonary disease. Lancet 379(9823):1341–1351CrossRefGoogle Scholar
  15. Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P et al (1998) Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 158(4):1277–1285CrossRefGoogle Scholar
  16. Di Stefano A, Caramori G, Oates T, Capelli A, Lusuardi M, Gnemmi I et al (2002) Increased expression of nuclear factor-kappaB in bronchial biopsies from smokers and patients with COPD. Eur Respir J 20(3):556–563CrossRefGoogle Scholar
  17. Donnelly LE, Barnes PJ (2012) Defective phagocytosis in airways disease. Chest 141(4):1055–1062CrossRefGoogle Scholar
  18. Fischer BM, Voynow JA, Ghio AJ (2015) COPD: balancing oxidants and antioxidants. Int J Chron Obstruct Pulmon Dis 10:261–276CrossRefGoogle Scholar
  19. Gadek JE, Fells GA, Zimmerman RL, Rennard SI, Crystal RG (1981) Antielastases of the human alveolar structures. Implications for the protease-antiprotease theory of emphysema. J Clin Invest 68(4):889–898CrossRefGoogle Scholar
  20. Ginzberg HH, Cherapanov V, Dong Q, Cantin A, McCulloch CA, Shannon PT et al (2001) Neutrophil-mediated epithelial injury during transmigration: role of elastase. Am J Physiol Gastrointest Liver Physiol 281(3):G705–G717CrossRefGoogle Scholar
  21. Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589–598CrossRefGoogle Scholar
  22. Harju T, Kaarteenaho-Wiik R, Soini Y, Sormunen R, Kinnula VL (2002) Diminished immunoreactivity of gamma-glutamylcysteine synthetase in the airways of smokers’ lung. Am J Respir Crit Care Med 166(5):754–759CrossRefGoogle Scholar
  23. Hayat M (2014) Autophagy: cancer, other pathologies, inflammation, immunity, infection and aging, 1st edn. Academic, San DiegoGoogle Scholar
  24. Horvath I, MacNee W, Kelly FJ, Dekhuijzen PN, Phillips M, Doring G et al (2001) “Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases”, summary of the ERS research seminar in Budapest, Hungary, September, 1999. Eur Respir J 18(2):420–430CrossRefGoogle Scholar
  25. Huang K, Fingar DC (2014) Growing knowledge of the mTOR signaling network. Semin Cell Dev Biol 36:79–90CrossRefGoogle Scholar
  26. Hwang JW, Rajendrasozhan S, Yao H, Chung S, Sundar IK, Huyck HL et al (2011) FOXO3 deficiency leads to increased susceptibility to cigarette smoke-induced inflammation, airspace enlargement, and chronic obstructive pulmonary disease. J Immunol 187(2):987–998CrossRefGoogle Scholar
  27. Ito K, Hanazawa T, Tomita K, Barnes PJ, Adcock IM (2004) Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration. Biochem Biophys Res Commun 315(1):240–245CrossRefGoogle Scholar
  28. Kirkham PA, Barnes PJ (2013) Oxidative stress in COPD. Chest 144(1):266–273CrossRefGoogle Scholar
  29. Kirkham PA, Spooner G, Rahman I, Rossi AG (2004) Macrophage phagocytosis of apoptotic neutrophils is compromised by matrix proteins modified by cigarette smoke and lipid peroxidation products. Biochem Biophys Res Commun 318(1):32–37CrossRefGoogle Scholar
  30. Kluchova Z, Petrasova D, Joppa P, Dorkova Z, Tkacova R (2007) The association between oxidative stress and obstructive lung impairment in patients with COPD. Physiol Res 56(1):51–56PubMedGoogle Scholar
  31. Kobayashi M, Yamamoto M (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzym Regul 46:113–140CrossRefGoogle Scholar
  32. Kodgule R, Salvi S (2012) Exposure to biomass smoke as a cause for airway disease in women and children. Curr Opin Allergy Clin Immunol 12(1):82–90CrossRefGoogle Scholar
  33. Korkmaz B, Moreau T, Gauthier F (2008) Neutrophil elastase, proteinase 3 and cathepsin G: physicochemical properties, activity and physiopathological functions. Biochimie 90(2):227–242CrossRefGoogle Scholar
  34. Kuiper JW, Sun C, Magalhaes MA, Glogauer M (2011) Rac regulates PtdInsP(3) signaling and the chemotactic compass through a redox-mediated feedback loop. Blood 118(23):6164–6171CrossRefGoogle Scholar
  35. Liu Y, Fiskum G, Schubert D (2002) Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 80(5):780–787CrossRefGoogle Scholar
  36. Marotta F, Naito Y, Padrini F, Xuewei X, Jain S, Soresi V et al (2011) Redox balance signalling in occupational stress: modification by nutraceutical intervention. J Biol Regul Homeost Agents 25(2):221–229PubMedGoogle Scholar
  37. Matheson NR, Wong PS, Travis J (1979) Enzymatic inactivation of human alpha-1-proteinase inhibitor by neutrophil myeloperoxidase. Biochem Biophys Res Commun 88(2):402–409CrossRefGoogle Scholar
  38. McGuinness AJ, Sapey E (2017) Oxidative stress in COPD: sources, markers, and potential mechanisms. J Clin Med 6(2)CrossRefGoogle Scholar
  39. Meja KK, Rajendrasozhan S, Adenuga D, Biswas SK, Sundar IK, Spooner G et al (2008) Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol 39(3):312–323CrossRefGoogle Scholar
  40. Menon B, Singh M, Ross RS, Johnson JN, Singh K (2006) beta-adrenergic receptor-stimulated apoptosis in adult cardiac myocytes involves MMP-2-mediated disruption of beta1 integrin signaling and mitochondrial pathway. Am J Physiol Cell Physiol 290(1):C254–C261CrossRefGoogle Scholar
  41. Meo SA, Suraya F (2015) Effect of environmental air pollution on cardiovascular diseases. Eur Rev Med Pharmacol Sci 19(24):4890–4897PubMedGoogle Scholar
  42. Michaeloudes C, Sukkar MB, Khorasani NM, Bhavsar PK, Chung KF (2011) TGF-beta regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 300(2):L295–L304CrossRefGoogle Scholar
  43. Mirza S, Clay RD, Koslow MA, Scanlon PD (2018) COPD guidelines: a review of the 2018 GOLD report. Mayo Clin Proc 93(10):1488–1502CrossRefGoogle Scholar
  44. Mohan S, Ho T, Kjarsgaard M, Radford K, Borhan AS, Thabane L et al (2017) Hemosiderin in sputum macrophages may predict infective exacerbations of chronic obstructive pulmonary disease: a retrospective observational study. BMC Pulm Med 17(1):60CrossRefGoogle Scholar
  45. Nakamaru Y, Vuppusetty C, Wada H, Milne JC, Ito M, Rossios C et al (2009) A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J 23(9):2810–2819CrossRefGoogle Scholar
  46. Negre-Salvayre A, Coatrieux C, Ingueneau C, Salvayre R (2008) Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br J Pharmacol 153(1):6–20CrossRefGoogle Scholar
  47. Noguera A, Batle S, Miralles C, Iglesias J, Busquets X, MacNee W et al (2001) Enhanced neutrophil response in chronic obstructive pulmonary disease. Thorax 56(6):432–437CrossRefGoogle Scholar
  48. Philippot Q, Deslee G, Adair-Kirk TL, Woods JC, Byers D, Conradi S et al (2014) Increased iron sequestration in alveolar macrophages in chronic obstructive pulmonary disease. PLoS One 9(5):e96285CrossRefGoogle Scholar
  49. Plautz MW, Bailey K, Wesselius LJ (2000) Influence of cigarette smoking on crocidolite-induced ferritin release by human alveolar macrophages. J Lab Clin Med 136(6):449–456CrossRefGoogle Scholar
  50. Rahman I, Adcock IM (2006) Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J 28(1):219–242CrossRefGoogle Scholar
  51. Rahman I, Morrison D, Donaldson K, MacNee W (1996) Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med 154(4 Pt 1):1055–1060CrossRefGoogle Scholar
  52. Rahman I, van Schadewijk AA, Crowther AJ, Hiemstra PS, Stolk J, MacNee W et al (2002) 4-Hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 166(4):490–495CrossRefGoogle Scholar
  53. Rahman I, Biswas SK, Jimenez LA, Torres M, Forman HJ (2005) Glutathione, stress responses, and redox signaling in lung inflammation. Antioxid Redox Signal 7(1–2):42–59CrossRefGoogle Scholar
  54. Renkema TE, Postma DS, Noordhoek JA, Sluiter HJ, Kauffman HF (1993) Influence of in vivo prednisolone on increased in vitro O2− generation by neutrophils in emphysema. Eur Respir J 6(1):90–95PubMedGoogle Scholar
  55. Richens TR, Linderman DJ, Horstmann SA, Lambert C, Xiao YQ, Keith RL et al (2009) Cigarette smoke impairs clearance of apoptotic cells through oxidant-dependent activation of RhoA. Am J Respir Crit Care Med 179(11):1011–1021CrossRefGoogle Scholar
  56. Russell RE, Thorley A, Culpitt SV, Dodd S, Donnelly LE, Demattos C et al (2002) Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases. Am J Physiol Lung Cell Mol Physiol 283(4):L867–L873CrossRefGoogle Scholar
  57. Salama SA, Snapka RM (2012) Amino acid chloramine damage to proliferating cell nuclear antigen in mammalian cells. In Vivo 26(4):501–517PubMedPubMedCentralGoogle Scholar
  58. Sapey E, Stockley JA, Greenwood H, Ahmad A, Bayley D, Lord JM et al (2011) Behavioral and structural differences in migrating peripheral neutrophils from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 183(9):1176–1186CrossRefGoogle Scholar
  59. Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N et al (2014) Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 123(2):239–248CrossRefGoogle Scholar
  60. Scheffler IE (2007) Structure and morphology: integration into the cell. In: Scheffler IE (ed) Mitochondria. 2. Wiley, New York, pp 15–47CrossRefGoogle Scholar
  61. Shi MM, Iwamoto T, Forman HJ (1994) Gamma-Glutamylcysteine synthetase and GSH increase in quinone-induced oxidative stress in BPAEC. Am J Phys 267(4 Pt 1):L414–L421Google Scholar
  62. Siu GM, Draper HH (1982) Metabolism of malonaldehyde in vivo and in vitro. Lipids 17(5):349–355CrossRefGoogle Scholar
  63. Tager M, Piecyk A, Kohnlein T, Thiel U, Ansorge S, Welte T (2000) Evidence of a defective thiol status of alveolar macrophages from COPD patients and smokers. Chronic obstructive pulmonary disease. Free Radic Biol Med 29(11):1160–1165CrossRefGoogle Scholar
  64. Takeyama K, Agusti C, Ueki I, Lausier J, Cardell LO, Nadel JA (1998) Neutrophil-dependent goblet cell degranulation: role of membrane-bound elastase and adhesion molecules. Am J Phys 275(2. Pt 1):L294–L302Google Scholar
  65. Tang Z, Baykal AT, Gao H, Quezada HC, Zhang H, Bereczki E et al (2014) mTor is a signaling hub in cell survival: a mass-spectrometry-based proteomics investigation. J Proteome Res 13(5):2433–2444CrossRefGoogle Scholar
  66. Tomaki M, Sugiura H, Koarai A, Komaki Y, Akita T, Matsumoto T et al (2007) Decreased expression of antioxidant enzymes and increased expression of chemokines in COPD lung. Pulm Pharmacol Ther 20(5):596–605CrossRefGoogle Scholar
  67. Tzagoloff A (1982) Mitochondrial structure and compartmentalization. In: Press P (ed) Mitochondria. Springer Link, New York, pp 15–38Google Scholar
  68. van der Toorn M, Rezayat D, Kauffman HF, Bakker SJ, Gans RO, Koeter GH et al (2009) Lipid-soluble components in cigarette smoke induce mitochondrial production of reactive oxygen species in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 297(1):L109–L114CrossRefGoogle Scholar
  69. Vandivier RW, Fadok VA, Hoffmann PR, Bratton DL, Penvari C, Brown KK et al (2002) Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 109(5):661–670CrossRefGoogle Scholar
  70. Vandivier RW, Henson PM, Douglas IS (2006) Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 129(6):1673–1682CrossRefGoogle Scholar
  71. Wesselius LJ, Nelson ME, Skikne BS (1994) Increased release of ferritin and iron by iron-loaded alveolar macrophages in cigarette smokers. Am J Respir Crit Care Med 150(3):690–695CrossRefGoogle Scholar
  72. Yao H, Rahman I (2011) Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease. Toxicol Appl Pharmacol 254(2):72–85CrossRefGoogle Scholar
  73. Yoon YS, Yoon DS, Lim IK, Yoon SH, Chung HY, Rojo M et al (2006) Formation of elongated giant mitochondria in DFO-induced cellular senescence: involvement of enhanced fusion process through modulation of Fis1. J Cell Physiol 209(2):468–480CrossRefGoogle Scholar
  74. Zhang X, Shan P, Homer R, Zhang Y, Petrache I, Mannam P et al (2014) Cathepsin E promotes pulmonary emphysema via mitochondrial fission. Am J Pathol 184(10):2730–2741CrossRefGoogle Scholar
  75. Zhou HZ, Ma X, Gray MO, Zhu BQ, Nguyen AP, Baker AJ et al (2007) Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction. Biochem Biophys Res Commun 358(1):189–195CrossRefGoogle Scholar
  76. Zinellu E, Zinellu A, Fois AG, Carru C, Pirina P (2016) Circulating biomarkers of oxidative stress in chronic obstructive pulmonary disease: a systematic review. Respir Res 17(1):150CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Mariana A. Antunes
    • 1
  • Fernanda F. Cruz
    • 1
  • Patricia R. M. Rocco
    • 1
  1. 1.Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of BiophysicsFederal University of Rio de Janeiro, Centro de Ciências da SaúdeRio de JaneiroBrazil

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