Logo of thoraxThoraxVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
Thorax. Apr 2005; 60(4): 293–300.
PMCID: PMC1747355

Oxidative stress and airway inflammation in severe exacerbations of COPD


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 (187K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Keatings VM, Barnes PJ. 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. [PubMed]
  • Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000 Feb;55(2):114–120. [PMC free article] [PubMed]
  • Paredi P, Kharitonov SA, Leak D, Ward S, Cramer D, Barnes PJ. 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. [PubMed]
  • 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. [PubMed]
  • 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. [PubMed]
  • Pesci A, Balbi B, Majori M, Cacciani G, Bertacco S, Alciato P, Donner CF. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J. 1998 Aug;12(2):380–386. [PubMed]
  • 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. [PubMed]
  • MacNee W, Wiggs B, Belzberg AS, Hogg JC. The effect of cigarette smoking on neutrophil kinetics in human lungs. N Engl J Med. 1989 Oct 5;321(14):924–928. [PubMed]
  • Selby C, Drost E, Lannan S, Wraith PK, MacNee W. Neutrophil retention in the lungs of patients with chronic obstructive pulmonary disease. Am Rev Respir Dis. 1991 Jun;143(6):1359–1364. [PubMed]
  • Drost EM, Selby C, Bridgeman MM, MacNee W. Decreased leukocyte deformability after acute cigarette smoking in humans. Am Rev Respir Dis. 1993 Nov;148(5):1277–1283. [PubMed]
  • Li XY, 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. [PubMed]
  • Cantin AM, North SL, Hubbard RC, Crystal RG. Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol (1985) 1987 Jul;63(1):152–157. [PubMed]
  • Rahman I, Smith CA, Lawson MF, Harrison DJ, 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. [PubMed]
  • Donaldson GC, Seemungal TAR, Patel IS, Lloyd-Owen SJ, Wilkinson TMA, Wedzicha JA. Longitudinal changes in the nature, severity and frequency of COPD exacerbations. Eur Respir J. 2003 Dec;22(6):931–936. [PubMed]
  • Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. 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. [PubMed]
  • Celli BR, MacNee W. 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. [PubMed]
  • Kelly CA, Kotre CJ, Ward C, Hendrick DJ, Walters EH. Anatomical distribution of bronchoalveolar lavage fluid as assessed by digital subtraction radiography. Thorax. 1987 Aug;42(8):624–628. [PMC free article] [PubMed]
  • 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. [PubMed]
  • 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. [PubMed]
  • Andrews NC, Faller DV. 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. [PMC free article] [PubMed]
  • Gilmour PS, Brown DM, Beswick PH, 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. [PMC free article] [PubMed]
  • 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, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004 Jun 24;350(26):2645–2653. [PubMed]
  • Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, Mapp CE, Fabbri LM, Donner CF, 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. [PubMed]
  • Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, Dales RE. 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. [PubMed]
  • Linden M, Rasmussen JB, Piitulainen E, Tunek A, Larson M, Tegner H, Venge P, Laitinen LA, Brattsand R. Airway inflammation in smokers with nonobstructive and obstructive chronic bronchitis. Am Rev Respir Dis. 1993 Nov;148(5):1226–1232. [PubMed]
  • Peleman RA, Rytilä PH, Kips JC, Joos GF, Pauwels RA. The cellular composition of induced sputum in chronic obstructive pulmonary disease. Eur Respir J. 1999 Apr;13(4):839–843. [PubMed]
  • Yildiz F, Kaur AC, 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. [PubMed]
  • Keatings VM, Collins PD, Scott DM, Barnes PJ. 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. [PubMed]
  • 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. [PMC free article] [PubMed]
  • 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 Oct 15;168(8):968–975. [PubMed]
  • Saetta M, Di Stefano A, Maestrelli P, Turato G, Ruggieri MP, Roggeri A, Calcagni P, Mapp CE, Ciaccia A, Fabbri LM. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 1):1646–1652. [PubMed]
  • Nocker RE, Schoonbrood DF, van de Graaf EA, Hack CE, Lutter R, Jansen HM, Out TA. Interleukin-8 in airway inflammation in patients with asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol. 1996 Feb;109(2):183–191. [PubMed]
  • Richman-Eisenstat JB, Jorens PG, Hébert CA, Ueki I, Nadel JA. 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. [PubMed]
  • 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. [PubMed]
  • Woolhouse IS, Bayley DL, Stockley RA. Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis. Thorax. 2002 Aug;57(8):667–671. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Roebuck KA. Regulation of interleukin-8 gene expression. J Interferon Cytokine Res. 1999 May;19(5):429–438. [PubMed]
  • Vayssier M, Favatier F, Pinot F, Bachelet M, Polla BS. 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. [PubMed]
  • Favatier F, Polla BS. 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. [PMC free article] [PubMed]
  • 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. [PubMed]
  • 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 15;101(24):8945–8950. [PMC free article] [PubMed]
  • Korn SH, Wouters EF, Vos N, Janssen-Heininger YM. Cytokine-induced activation of nuclear factor-kappa B is inhibited by hydrogen peroxide through oxidative inactivation of IkappaB kinase. J Biol Chem. 2001 Sep 21;276(38):35693–35700. [PubMed]
  • 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. [PubMed]
  • Koul A, Bhatia V, Bansal MP. Effect of alpha-tocopherol on pulmonary antioxidant defence system and lipid peroxidation in cigarette smoke inhaling mice. BMC Biochem. 2001;2:14–14. [PMC free article] [PubMed]
  • Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M, Kharitonov SA, Barnes PJ. 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. [PubMed]
  • 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. [PubMed]

Articles from Thorax are provided here courtesy of BMJ Group


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...