Skip to main content
PMC home page
Thorax logoLink to Thorax
. 2005 Apr;60(4):293–300. doi: 10.1136/thx.2004.027946

Oxidative stress and airway inflammation in severe exacerbations of COPD

E Drost 1, K Skwarski 1, J Sauleda 1, N Soler 1, J Roca 1, A Agusti 1, W MacNee 1
PMCID: PMC1747355  PMID: 15790984

Abstract

Background: A study was undertaken to assess both oxidative stress and inflammation in the lungs of patients with chronic obstructive pulmonary disease (COPD) during severe and very severe exacerbations compared with those with stable COPD, healthy smokers, and non-smokers. Two sites within the lungs were compared: the large airways (in sputum) and the peripheral airways (by bronchoalveolar lavage (BAL)).

Methods: BAL fluid cell numbers and levels of tumour necrosis factor (TNFα) and interleukin (IL)-8 were measured as markers of airway inflammation and glutathione (GSH) levels as a marker of antioxidant status. Nuclear translocation of the pro-inflammatory transcription factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) were also measured by electromobility shift assay in BAL fluid leucocytes and lung biopsy samples.

Results: Influx of inflammatory cells into the peripheral airways during exacerbations of COPD was confirmed. Increased IL-8 levels were detected in BAL fluid from patients with stable COPD compared with non-smokers and healthy smokers, with no further increase during exacerbations. In contrast, IL-8 levels in the large airways increased during exacerbations. GSH levels were increased in the BAL fluid of smokers (444%) and patients with stable COPD (235%) compared with non-smokers and were reduced during exacerbations (severe 89.2%; very severe 52.3% compared with stable COPD). NF-κB DNA binding in BAL leucocytes was decreased in healthy smokers compared with non-smokers (41.3%, n = 9, p<0.001) but did not differ in COPD patients, whereas AP-1 DNA binding was significantly decreased during exacerbations of COPD.

Conclusion: There is evidence of increased oxidative stress in the airways of patients with COPD that is increased further in severe and very severe exacerbations of the disease. This is associated with increased neutrophil influx and IL-8 levels during exacerbations.

Full Text

The Full Text of this article is available as a PDF (186.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aaron S. D., Angel J. B., Lunau M., Wright K., Fex C., Le Saux N., Dales R. E. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001 Feb;163(2):349–355. doi: 10.1164/ajrccm.163.2.2003122. [DOI] [PubMed] [Google Scholar]
  2. Andrews N. C., Faller D. V. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 1991 May 11;19(9):2499–2499. doi: 10.1093/nar/19.9.2499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bhowmik A., Seemungal T. A., Sapsford R. J., Wedzicha J. A. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000 Feb;55(2):114–120. doi: 10.1136/thorax.55.2.114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cantin A. M., North S. L., Hubbard R. C., Crystal R. G. Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol (1985) 1987 Jul;63(1):152–157. doi: 10.1152/jappl.1987.63.1.152. [DOI] [PubMed] [Google Scholar]
  5. Celli B. R., MacNee W., ATS/ERS Task Force Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004 Jun;23(6):932–946. doi: 10.1183/09031936.04.00014304. [DOI] [PubMed] [Google Scholar]
  6. Di Stefano A., Capelli A., Lusuardi M., Balbo P., Vecchio C., Maestrelli P., Mapp C. E., Fabbri L. M., Donner C. F., Saetta M. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med. 1998 Oct;158(4):1277–1285. doi: 10.1164/ajrccm.158.4.9802078. [DOI] [PubMed] [Google Scholar]
  7. Donaldson G. C., Seemungal T. A. R., Patel I. S., Lloyd-Owen S. J., Wilkinson T. M. A., Wedzicha J. A. Longitudinal changes in the nature, severity and frequency of COPD exacerbations. Eur Respir J. 2003 Dec;22(6):931–936. doi: 10.1183/09031936.03.00038303. [DOI] [PubMed] [Google Scholar]
  8. Drost E. M., Selby C., Bridgeman M. M., MacNee W. Decreased leukocyte deformability after acute cigarette smoking in humans. Am Rev Respir Dis. 1993 Nov;148(5):1277–1283. doi: 10.1164/ajrccm/148.5.1277. [DOI] [PubMed] [Google Scholar]
  9. Favatier F., Polla B. S. Tobacco-smoke-inducible human haem oxygenase-1 gene expression: role of distinct transcription factors and reactive oxygen intermediates. Biochem J. 2001 Feb 1;353(Pt 3):475–482. doi: 10.1042/0264-6021:3530475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gilmour P. S., Brown D. M., Beswick P. H., MacNee W., Rahman I., Donaldson K. Free radical activity of industrial fibers: role of iron in oxidative stress and activation of transcription factors. Environ Health Perspect. 1997 Sep;105 (Suppl 5):1313–1317. doi: 10.1289/ehp.97105s51313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hirota K., Murata M., Sachi Y., Nakamura H., Takeuchi J., Mori K., Yodoi J. Distinct roles of thioredoxin in the cytoplasm and in the nucleus. A two-step mechanism of redox regulation of transcription factor NF-kappaB. J Biol Chem. 1999 Sep 24;274(39):27891–27897. doi: 10.1074/jbc.274.39.27891. [DOI] [PubMed] [Google Scholar]
  12. Hogg James C., Chu Fanny, Utokaparch Soraya, Woods Ryan, Elliott W. Mark, Buzatu Liliana, Cherniack Ruben M., Rogers Robert M., Sciurba Frank C., Coxson Harvey O. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004 Jun 24;350(26):2645–2653. doi: 10.1056/NEJMoa032158. [DOI] [PubMed] [Google Scholar]
  13. Keatings V. M., Barnes P. J. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am J Respir Crit Care Med. 1997 Feb;155(2):449–453. doi: 10.1164/ajrccm.155.2.9032177. [DOI] [PubMed] [Google Scholar]
  14. Keatings V. M., Collins P. D., Scott D. M., Barnes P. J. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med. 1996 Feb;153(2):530–534. doi: 10.1164/ajrccm.153.2.8564092. [DOI] [PubMed] [Google Scholar]
  15. Kelly C. A., Kotre C. J., Ward C., Hendrick D. J., Walters E. H. Anatomical distribution of bronchoalveolar lavage fluid as assessed by digital subtraction radiography. Thorax. 1987 Aug;42(8):624–628. doi: 10.1136/thx.42.8.624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Korn S. H., Wouters E. F., Vos N., Janssen-Heininger Y. M. Cytokine-induced activation of nuclear factor-kappa B is inhibited by hydrogen peroxide through oxidative inactivation of IkappaB kinase. J Biol Chem. 2001 Jul 30;276(38):35693–35700. doi: 10.1074/jbc.M104321200. [DOI] [PubMed] [Google Scholar]
  17. Koul A., Bhatia V., Bansal M. P. Effect of alpha-tocopherol on pulmonary antioxidant defence system and lipid peroxidation in cigarette smoke inhaling mice. BMC Biochem. 2001 Nov 16;2:14–14. doi: 10.1186/1471-2091-2-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Li X. Y., Donaldson K., Rahman I., MacNee W. An investigation of the role of glutathione in increased epithelial permeability induced by cigarette smoke in vivo and in vitro. Am J Respir Crit Care Med. 1994 Jun;149(6):1518–1525. doi: 10.1164/ajrccm.149.6.8004308. [DOI] [PubMed] [Google Scholar]
  19. Linden M., Rasmussen J. B., Piitulainen E., Tunek A., Larson M., Tegner H., Venge P., Laitinen L. A., Brattsand R. Airway inflammation in smokers with nonobstructive and obstructive chronic bronchitis. Am Rev Respir Dis. 1993 Nov;148(5):1226–1232. doi: 10.1164/ajrccm/148.5.1226. [DOI] [PubMed] [Google Scholar]
  20. MacNee W., Wiggs B., Belzberg A. S., Hogg J. C. The effect of cigarette smoking on neutrophil kinetics in human lungs. N Engl J Med. 1989 Oct 5;321(14):924–928. doi: 10.1056/NEJM198910053211402. [DOI] [PubMed] [Google Scholar]
  21. Montuschi P., Collins J. V., Ciabattoni G., Lazzeri N., Corradi M., Kharitonov S. A., Barnes P. J. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):1175–1177. doi: 10.1164/ajrccm.162.3.2001063. [DOI] [PubMed] [Google Scholar]
  22. Morrison D., Rahman I., Lannan S., MacNee W. Epithelial permeability, inflammation, and oxidant stress in the air spaces of smokers. Am J Respir Crit Care Med. 1999 Feb;159(2):473–479. doi: 10.1164/ajrccm.159.2.9804080. [DOI] [PubMed] [Google Scholar]
  23. Nishikawa M., Kakemizu N., Ito T., Kudo M., Kaneko T., Suzuki M., Udaka N., Ikeda H., Okubo T. Superoxide mediates cigarette smoke-induced infiltration of neutrophils into the airways through nuclear factor-kappaB activation and IL-8 mRNA expression in guinea pigs in vivo. Am J Respir Cell Mol Biol. 1999 Feb;20(2):189–198. doi: 10.1165/ajrcmb.20.2.3305. [DOI] [PubMed] [Google Scholar]
  24. Nocker R. E., Schoonbrood D. F., van de Graaf E. A., Hack C. E., Lutter R., Jansen H. M., Out T. A. Interleukin-8 in airway inflammation in patients with asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol. 1996 Feb;109(2):183–191. doi: 10.1159/000237218. [DOI] [PubMed] [Google Scholar]
  25. Paredi P., Kharitonov S. A., Leak D., Ward S., Cramer D., Barnes P. J. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):369–373. doi: 10.1164/ajrccm.162.2.9909025. [DOI] [PubMed] [Google Scholar]
  26. Pauwels R. A., Buist A. S., Calverley P. M., Jenkins C. R., Hurd S. S., GOLD Scientific Committee Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001 Apr;163(5):1256–1276. doi: 10.1164/ajrccm.163.5.2101039. [DOI] [PubMed] [Google Scholar]
  27. Peleman R. A., Rytilä P. H., Kips J. C., Joos G. F., Pauwels R. A. The cellular composition of induced sputum in chronic obstructive pulmonary disease. Eur Respir J. 1999 Apr;13(4):839–843. doi: 10.1034/j.1399-3003.1999.13d24.x. [DOI] [PubMed] [Google Scholar]
  28. Pesci A., Balbi B., Majori M., Cacciani G., Bertacco S., Alciato P., Donner C. F. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J. 1998 Aug;12(2):380–386. doi: 10.1183/09031936.98.12020380. [DOI] [PubMed] [Google Scholar]
  29. Qiu Yusheng, Zhu Jie, Bandi Venkata, Atmar Robert L., Hattotuwa Keith, Guntupalli Kay K., Jeffery Peter K. Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003 Jul 11;168(8):968–975. doi: 10.1164/rccm.200208-794OC. [DOI] [PubMed] [Google Scholar]
  30. Rahman I., MacNee W. Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic Biol Med. 2000 May 1;28(9):1405–1420. doi: 10.1016/s0891-5849(00)00215-x. [DOI] [PubMed] [Google Scholar]
  31. Rahman I., Morrison D., Donaldson K., MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med. 1996 Oct;154(4 Pt 1):1055–1060. doi: 10.1164/ajrccm.154.4.8887607. [DOI] [PubMed] [Google Scholar]
  32. Rahman I., Smith C. A., Lawson M. F., Harrison D. J., MacNee W. Induction of gamma-glutamylcysteine synthetase by cigarette smoke is associated with AP-1 in human alveolar epithelial cells. FEBS Lett. 1996 Oct 28;396(1):21–25. doi: 10.1016/0014-5793(96)01027-7. [DOI] [PubMed] [Google Scholar]
  33. Reynaert Niki L., Ckless Karina, Korn Solange H., Vos Nanda, Guala Amy S., Wouters Emiel F. M., van der Vliet Albert, Janssen-Heininger Yvonne M. W. Nitric oxide represses inhibitory kappaB kinase through S-nitrosylation. Proc Natl Acad Sci U S A. 2004 Jun 7;101(24):8945–8950. doi: 10.1073/pnas.0400588101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Richman-Eisenstat J. B., Jorens P. G., Hébert C. A., Ueki I., Nadel J. A. Interleukin-8: an important chemoattractant in sputum of patients with chronic inflammatory airway diseases. Am J Physiol. 1993 Apr;264(4 Pt 1):L413–L418. doi: 10.1152/ajplung.1993.264.4.L413. [DOI] [PubMed] [Google Scholar]
  35. Roebuck K. A. Regulation of interleukin-8 gene expression. J Interferon Cytokine Res. 1999 May;19(5):429–438. doi: 10.1089/107999099313866. [DOI] [PubMed] [Google Scholar]
  36. Saetta M., Di Stefano A., Maestrelli P., Turato G., Ruggieri M. P., Roggeri A., Calcagni P., Mapp C. E., Ciaccia A., Fabbri L. M. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 1):1646–1652. doi: 10.1164/ajrccm.150.6.7952628. [DOI] [PubMed] [Google Scholar]
  37. Selby C., Drost E., Lannan S., Wraith P. K., MacNee W. Neutrophil retention in the lungs of patients with chronic obstructive pulmonary disease. Am Rev Respir Dis. 1991 Jun;143(6):1359–1364. doi: 10.1164/ajrccm/143.6.1359. [DOI] [PubMed] [Google Scholar]
  38. Soler N., Ewig S., Torres A., Filella X., Gonzalez J., Zaubet A. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur Respir J. 1999 Nov;14(5):1015–1022. doi: 10.1183/09031936.99.14510159. [DOI] [PubMed] [Google Scholar]
  39. Tanino M., Betsuyaku T., Takeyabu K., Tanino Y., Yamaguchi E., Miyamoto K., Nishimura M. Increased levels of interleukin-8 in BAL fluid from smokers susceptible to pulmonary emphysema. Thorax. 2002 May;57(5):405–411. doi: 10.1136/thorax.57.5.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem. 1969 Mar;27(3):502–522. doi: 10.1016/0003-2697(69)90064-5. [DOI] [PubMed] [Google Scholar]
  41. Vandeputte C., Guizon I., Genestie-Denis I., Vannier B., Lorenzon G. A microtiter plate assay for total glutathione and glutathione disulfide contents in cultured/isolated cells: performance study of a new miniaturized protocol. Cell Biol Toxicol. 1994 Dec;10(5-6):415–421. doi: 10.1007/BF00755791. [DOI] [PubMed] [Google Scholar]
  42. Vayssier M., Favatier F., Pinot F., Bachelet M., Polla B. S. Tobacco smoke induces coordinate activation of HSF and inhibition of NFkappaB in human monocytes: effects on TNFalpha release. Biochem Biophys Res Commun. 1998 Nov 9;252(1):249–256. doi: 10.1006/bbrc.1998.9586. [DOI] [PubMed] [Google Scholar]
  43. Woolhouse I. S., Bayley D. L., Stockley R. A. Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis. Thorax. 2002 Aug;57(8):667–671. doi: 10.1136/thorax.57.8.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yamamoto C., Yoneda T., Yoshikawa M., Fu A., Tokuyama T., Tsukaguchi K., Narita N. Airway inflammation in COPD assessed by sputum levels of interleukin-8. Chest. 1997 Aug;112(2):505–510. doi: 10.1378/chest.112.2.505. [DOI] [PubMed] [Google Scholar]
  45. Yildiz F., Kaur A. C., Ilgazli A., Celikoglu M., Kaçar Ozkara S., Paksoy N., Ozkarakaş O. Inhaled corticosteroids may reduce neutrophilic inflammation in patients with stable chronic obstructive pulmonary disease. Respiration. 2000;67(1):71–76. doi: 10.1159/000029466. [DOI] [PubMed] [Google Scholar]
  46. Zar Heather J., Hanslo David, Apolles Patricia, Swingler George, Hussey Gregory. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet. 2005 Jan 8;365(9454):130–134. doi: 10.1016/S0140-6736(05)17702-2. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES