Oxidative Stress in Obstructive and Restrictive Lung Diseases

  • Elena BargagliEmail author
  • Alfonso Carleo


The lung has ample and vascularized surface area constantly exposed to endogenous and environmental oxidants (in particular cigarette smoke). Thus, the imbalance between oxidants and antioxidant defenses has a pathologically important role in several lung disorders. This chapter describes the sources of free radical generation, ROS-induced signaling pathways, and mechanisms of oxidative stress damages in the pathogenesis of obstructive pulmonary diseases, idiopathic pulmonary fibrosis, and asthma. ROS are regulatory factors in different molecular pathways involved in miscellaneous lung diseases and might represent potential suggestions for therapeutic approaches. Given the limited effectiveness of current strategies, novel experimental approaches to develop improved antioxidant therapies are discussed.


Oxidative stress Damage mechanisms Lung diseases COPD IPF Asthma Antioxidant therapies 


Conflict of Interest

The authors declare no conflict of interest.


  1. 1.
    Ahmad S, Khan MY, Rafi Z et al (2018) Oxidation, glycation and glycoxidation – the vicious cycle and lung cancer. Semin Cancer Biol 49:29–36PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Gawda A, Majka G, Nowak B et al (2017) Air pollution, oxidative stress, and exacerbation of autoimmune diseases. Cent Eur J Immunol 42(3):305–312PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Bargagli E, Lavorini F, Pistolesi M et al (2017) Trace metals in fluids lining the respiratory system of patients with idiopathic pulmonary fibrosis and diffuse lung diseases. J Trace Elem Med Biol 42:39–44PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Fois AG, Paliogiannis P, Sotgia S et al (2018) Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications: a systematic review. Respir Res 19(1):51PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Johannson KA, Balmes JR, Collard HR (2015) Air pollution exposure: a novel environmental risk factor for interstitial lung disease? Chest 147(4):1161–1167PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Bargagli E, Olivieri C, Bennett D et al (2009) Oxidative stress in the pathogenesis of diffuse lung diseases: a review. Respir Med 103(9):1245–1256PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Boukhenouna S, Wilson MA, Bahmed K et al (2018) Reactive oxygen species in chronic obstructive pulmonary disease. Oxidative Med Cell Longev 2018:5730395CrossRefGoogle Scholar
  8. 8.
    Nardi J, Nascimento S, Göethel G et al (2018) Inflammatory and oxidative stress parameters as potential early biomarkers for silicosis. Clin Chim Acta 484:305–313PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Bullone M, Lavoie JP (2017) The contribution of oxidative stress and inflamm-aging in human and equine asthma. Int J Mol Sci 18(12):2612PubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bast A, Weseler AR, Haenen GR et al (2010) Oxidative stress and antioxidants in interstitial lung disease. Curr Opin Pulm Med 16(5):516–520PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Chatterjee S, Nieman GF, Christie JD et al (2014) Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307(9):L668–L680PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Evans CE, Zhao YY (2017) Molecular basis of nitrative stress in the pathogenesis of pulmonary hypertension. Adv Exp Med Biol 967:33–45PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Gonzalez-Gonzalez FJ, Chandel NS, Jain M et al (2017) Reactive oxygen species as signaling molecules in the development of lung fibrosis. Transl Res 190:61–68PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Ferrari RS, Andrade CF (2015) Oxidative stress and lung ischemia-reperfusion injury. Oxidative Med Cell Longev 2015:590987CrossRefGoogle Scholar
  15. 15.
    Barnes PJ (2017) Cellular and molecular mechanisms of asthma and COPD. Clin Sci 31(13):1541–1558CrossRefGoogle Scholar
  16. 16.
    Dai X, Bowatte G, Lowe AJ et al (2018) Do glutathione s-transferase genes modify the link between indoor air pollution and asthma, allergies, and lung function? A systematic review. Curr Allergy Asthma Rep 18(3):20PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Strzelak A, Ratajczak A, Adamiec A et al (2018) Tobacco smoke induces and alters immune responses in the lung triggering inflammation, allergy, asthma and other lung diseases: a mechanistic review. Int J Environ Res Public Health 15(5):E1033PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Evan GI, d’Adda di Fagagna F (2009) Cellular senescence: hot or what? Curr Opin Genet Dev 19(1):25–31PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Faner R, Rojas M, Macnee W, Agustí A (2012) Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 186(4):306–313CrossRefGoogle Scholar
  20. 20.
    Lawson WE, Cheng DS, Degryse AL et al (2011) Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. Proc Natl Acad Sci U S A 108(26):10562–10567PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Korfei M, Schmitt S, Ruppert C et al (2011) Comparative proteomic analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and lung transplant donor lungs. J Proteome Res 10:2185–2205PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Chen AC, Burr L, McGuckin MA (2018) Oxidative and endoplasmic reticulum stress in respiratory disease. Clin Transl Immunol 7(6):e1019CrossRefGoogle Scholar
  23. 23.
    Araya J, Kojima J, Takasaka N et al (2013) Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 304(1):L56–L69PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Scherz-Shouval R, Shvets E, Fass E et al (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26(7):1749–1760PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Kim SJ, Cheresh P, Jablonski RP, Williams DB et al (2015) The role of mitochondrial DNA in mediating alveolar epithelial cell apoptosis and pulmonary fibrosis. Int J Mol Sci 16(9):21486–21519PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Liu X, Chen Z (2017) The pathophysiological role of mitochondrial oxidative stress in lung diseases. J Transl Med 15(1):207PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Ng KKF, Nicholson AG, Harrison CL et al (2017) Is mitochondrial dysfunction a driving mechanism linking COPD to nonsmall cell lung carcinoma? Eur Respir Rev 26(146):170040CrossRefGoogle Scholar
  28. 28.
    Michaeloudes C, Bhavsar PK, Mumby S et al (2017) Dealing with stress: defective metabolic adaptation in chronic obstructive pulmonary disease pathogenesis. Ann Am Thorac Soc 14:S374–S382PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    van der Vliet A, Janssen-Heininger YMW, Anathy V (2018) Oxidative stress in chronic lung disease: from mitochondrial dysfunction to dysregulated redox signaling. Mol Asp Med 63:59–69CrossRefGoogle Scholar
  30. 30.
    Rubinsztein DC, Mariño G, Kroemer G (2011) Autophagy and aging. Cell 146:682–695PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Ascher K, Elliot SJ, Rubio GA et al (2017) Lung diseases of the elderly: cellular mechanisms. Clin Geriatr Med 33(4):473–490PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Freund A, Orjalo AV, Desprez PY et al (2010) Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med 16:238–246PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Minagawa S, Araya J, Numata T et al (2011) Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-ß-induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 300:L391–L401PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Chilosi M, Carloni A, Rossi A et al (2013) Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl Res 162(3):156–173CrossRefGoogle Scholar
  35. 35.
    Navarro S, Driscoll B (2017) Regeneration of the aging lung: a mini-review. Gerontology 63(3):270–280PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Liguori I, Russo G, Curcio F et al (2018) Oxidative stress, aging, and diseases. Clin Interv Aging 13:757–772PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Sethi GS, Dharwal V, Naura AS (2017) Poly(ADP-Ribose)Polymerase-1 in lung inflammatory disorders: a review. Front Immunol 8:1172PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kapellos TS, Bassler K, Aschenbrenner AC (2018) Dysregulated functions of lung macrophage populations in COPD. J Immunol Res 2018:2349045PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Alexandrov LB, Ju YS, Haase K et al (2016) Mutational signatures associated with tobacco smoking in human cancer. Science 354(6312):618–622PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Mariani TJ (2016) Respiratory disorders: ironing out smoking-related airway disease. Nature 531(7596):586–587PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Shi J, Li H, Yuan C et al (2018) Cigarette smoke-induced acquired dysfunction of cystic fibrosis transmembrane conductance regulator in the pathogenesis of chronic obstructive pulmonary disease. Oxidative Med Cell Longev 2018:6567578Google Scholar
  42. 42.
    Malaviya R, Laskin JD, Laskin DL (2017) Anti-TNFa therapy in inflammatory lung diseases. Pharmacol Ther 180:90–98PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Kliment CR, Oury TD (2010) Oxidative stress, extracellular matrix targets, and idiopathic pulmonary fibrosis. Free Radic Biol Med 49(5):707–717PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Zinellu A, Fois AG, Mangoni AA et al (2018) Systemic concentrations of asymmetric dimethylarginine (ADMA) in chronic obstructive pulmonary disease (COPD): state of the art. Amino Acids 50(9):1169–1176PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Landi C, Bargagli E, Carleo A et al (2014) A system biology study of BALF from patients affected by idiopathic pulmonary fibrosis (IPF) and healthy controls. Proteomics Clin Appl 8(11–12):932–950PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Kurotsu S, Tanaka K, Niino T et al (2014) Ameliorative effect of mepenzolate bromide against pulmonary fibrosis. J Pharmacol Exp Ther 350(1):79–88PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Schamberger AC, Schiller HB, Fernandez IE et al (2016) Glutathione peroxidase 3 localizes to the epithelial lining fluid and the extracellular matrix in interstitial lung disease. Sci Rep 6:29952PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Watson WH, Ritzenthaler JD, Roman J (2016) Lung extracellular matrix and redox regulation. Redox Biol 8:305–315PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Gorowiec MR, Borthwick LA, Parker SM et al (2012) Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-ß1-dependent mechanism. Free Radic Biol Med 52(6):1024–1032PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Zhou Y, Huang X, Hecker L et al (2013) Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest 123(3):1096–1108PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Fitch PM, Howie SE, Wallace WA (2011) Oxidative damage and TGF-ß differentially induce lung epithelial cell sonic hedgehog and tenascin-C expression: implications for the regulation of lung remodelling in idiopathic interstitial lung disease. Int J Exp Pathol 92(1):8–17PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Chen X, Shi C, Cao H et al (2018) The hedgehog and Wnt/ß-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis. Cell Death Dis 9(6):639PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Riedl MA, Nel AE (2008) Importance of oxidative stress in the pathogenesis and treatment of asthma. Curr Opin Allergy Clin Immunol 8(1):49–56PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Nadeem A, Siddiqui N, Alharbi NO et al (2014) Airway and systemic oxidant-antioxidant dysregulation in asthma: a possible scenario of oxidants spill over from lung into blood. Pulm Pharmacol Ther 29(1):31–40PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Villegas L, Stidham T, Nozik-Grayck E (2014) Oxidative stress and therapeutic development in lung diseases. J Pulm Respir Med 4(4):194PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Liu Z, Ren Z, Zhang J et al (2018) Role of ROS and nutritional antioxidants in human diseases. Front Physiol 9:477PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Burbank AJ, Duran CG, Pan Y et al (2018) Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin-induced sputum neutrophilia in volunteers with asthma. J Allergy Clin Immunol 141(4):1231–1238PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Oldham JM, Ma SF, Martinez FJ et al (2015) TOLLIP, MUC5B, and the response to N-Acetylcysteine among individuals with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 192(12):1475–1482PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Essat M, Harnan S, Gomersall T et al (2016) Fractional exhaled nitric oxide for the management of asthma in adults: a systematic review. Eur Respir J 47(3):751–768PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Polimanti R, Piacentini S, Moscatelli B et al (2010) GSTA1, GSTO1 and GSTO2 gene polymorphisms in Italian asthma patients. Clin Exp Pharmacol Physiol 37(8):870–872PubMedPubMedCentralGoogle Scholar
  61. 61.
    Gaurav R, Varasteh JT, Weaver MR et al (2017) The R213G polymorphism in SOD3 protects against allergic airway inflammation. JCI Insight 2(17):95072PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Department of Medicine, Surgery and NeurosciencesUniversity of SienaSienaItaly
  2. 2.Hannover Medical SchoolHannover UniversityHannoverGermany

Personalised recommendations