Skip to main content
Log in

Biomarkers of Systemic Inflammation in Stable and Exacerbation Phases of COPD

Lung Aims and scope Submit manuscript

Abstract

Apart from the deleterious effects on the lungs, chronic obstructive pulmonary disease (COPD) should be considered a complex, systemic disease involving several organs and systems. The nature and course of systemic inflammation in COPD is important since there is a potential for anti-inflammatory therapy. The objective of the current study was to assess biomarkers of systemic inflammation in stable and exacerbation phases of COPD patients as compared to healthy controls. We also investigated the course of these biomarkers after COPD exacerbation to evaluate their usefulness for disease monitoring. Eighty-three stable patients with moderate to very severe COPD, 20 patients in exacerbation phase, and 30 subjects with normal pulmonary function were included. Serum tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) levels were measured once in stable COPD patients and controls and three times in the COPD exacerbation group during follow-up. TNF-α and IL-6 levels were higher than in controls in both stable and exacerbation groups. Although NO was not higher in the stable COPD group than in controls, it was higher in the exacerbation group. In follow-up after the exacerbation period, significant alteration was not detected in cytokine or NO levels compared to admission. Raised serum levels of TNF-α and IL-6 support their use as biomarkers of the systemic inflammatory response in stable COPD patients. However, the circulating biomarkers we have studied are not found to be useful either as indicators of COPD exacerbation or for monitoring recovery after exacerbation.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) (updated 2005) Global strategy for the diagnosis, management and prevention of chronic obstructive lung disease. Available at http://www.goldcopd.com/

  2. Celli BR, MacNee W, ATS/ERS Task Force (2004) Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 23:932–946

    Google Scholar 

  3. Oudijk JD, Lammers WJ, Koenderman L (2003) Systemic inflammation in chronic obstructive pulmonary disease. Eur Respir J 22(Suppl 46):5s–13s

    Article  CAS  Google Scholar 

  4. Wouters EF, Creutzberg EC, Schols AM (2002) Systemic effects in COPD. Chest 121(Suppl):127s–130s

    Article  PubMed  Google Scholar 

  5. Agusti AGN, Noguera A, Sauleda J, Sala E, Pons J, Busquets X (2003) Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 21:347–360

    Article  PubMed  CAS  Google Scholar 

  6. Karadag F, Cildag O, Yurekli Y, Gurgey O (2003) Should COPD patients be routinely evaluated for bone mineral density? J Bone Miner Metab 21:243–247

    Google Scholar 

  7. Karadag F, Karul AB, Cildag O, Altun C, Gurgey O (2004) Determinants of BMI in patients with COPD. Respirology 9:70–75

    Article  PubMed  Google Scholar 

  8. Karadag F, Cildag O, Altınısık M, Kozacı LD, Kıter G, Altun C (2004) Trace elements as a component of oxidative stress in chronic obstructive pulmonary disease. Respirology 9:33–37

    Article  PubMed  Google Scholar 

  9. Karadag F, Polatli M, Ozcan H, Cildag O (2004) Role of arterial blood gas abnormalities on oedema formation in chronic obstructive pulmonary disease. Respirology 9:481–484

    Article  PubMed  Google Scholar 

  10. Karakas S, Karadag F, Karul AB, Gurgey O, Gurel S, Güney E, Cildag O (2005) Circulating leptin and body composition in chronic obstructive pulmonary disease. Int J Clin Pract 59:1167–1170

    Article  PubMed  CAS  Google Scholar 

  11. Karadag F, Ozcan H, Karul AB, Ceylan E, Cildag O (2007) Correlates of erectile dysfunction in moderate-to-severe chronic obstructive pulmonary disease. Respirology 112:248–253

    Article  Google Scholar 

  12. Karadag F, Ozcan H, Karul AB, Yilmaz M, Cildag O (2007) Correlates of non-thyroidal illness syndrome in chronic obstructive pulmonary disease. Respir Med 101:1439–1446

    Article  PubMed  Google Scholar 

  13. Gan WQ, Man SF, Senthilselvan A, Sin DD (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 59:574–580

    Article  PubMed  CAS  Google Scholar 

  14. Schols AM, Buurman WA, Staal van den Brekel AJ, Dentener MA, Wouters EF (1996) Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 51:819–824

    Article  PubMed  CAS  Google Scholar 

  15. Eid AA, Jonescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, Shale DJ (2001) Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164:1414–1418

    PubMed  CAS  Google Scholar 

  16. Chung KF (2001) Cytokines in chronic obstructive pulmonary disease. Eur Respir J 18(Suppl 34):50s–59s

    Article  CAS  Google Scholar 

  17. Ricciardolo FL, Di Stefano A, Sabatini F, Folkerts G (2006) Reactive nitrogen species in the respiratory tract. Eur J Pharmacol 533:240–252

    Article  PubMed  CAS  Google Scholar 

  18. Agusti AG, Villaverde JM, Togores B, Bosch M (1999) Serial measurements of exhaled nitric oxide during exacerbations of chronic obstructive pulmonary disease. Eur Respir J 4:523–528

    Article  Google Scholar 

  19. Kharitonov SA, Barnes PJ (2003) Nitric oxide, nitrotyrosine, and nitric oxide modulators in asthma and chronic obstructive pulmonary disease. Curr Allergy Asthma Rep 3:121–129

    Article  PubMed  Google Scholar 

  20. Barnes PJ, Stockley RA (2005) COPD: current therapeutic interventions and future approaches. Eur Respir J 25:1084–1106

    Article  PubMed  CAS  Google Scholar 

  21. Anthonisen NR, Connett JE, Enright PL, Manfreda J, Lung Health Study Research Group (2002) Hospitalizations and mortality in the Lung Health Study. Am J Respir Crit Care Med 166:333–339

    Article  PubMed  Google Scholar 

  22. ATS/ERS Task Force (2005) Standardization of lung function testing. Eur Respir J 26:319–338

    Article  Google Scholar 

  23. Aukrust P, Müller F, Lien E, Nordoy I, Liabakk N, Kvale D, Espevik T, Stig S (1999) Tumor necrosis factor (tnf) system levels in human immunodeficiency virus-infected patients during highly active antiretroviral therapy: persistent tnf activation is associated with virologic and immunologic treatment failure. J Infec Dis 179:74–82

    Article  CAS  Google Scholar 

  24. Navarro-Gonzalvez JA, Garcia-Benayas C, Arenas J (1998) Semiautomated measurement of nitrate in biological fluids. Clin Chem 44:679–681

    PubMed  CAS  Google Scholar 

  25. Ricciardolo FL, Caramori G, Ito K, Capelli A, Brun P, Abatangelo G, Papi A, Chung KF, Adcock I, Barnes PJ, Donner CF, Rossi A, Di Stefano A (2005) Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease. J Allergy Clin Immunol 116:1028–1035

    Article  PubMed  CAS  Google Scholar 

  26. Ebisui C, Tsujinaka T, Morimote T, Kan K, Iijima S, Yano M, Kominami E, Tanaka K, Monden M (1995) Interleukin-6 induces proteolysis by activating intracellular proteases in C2C12 myotubes. Clin Sci 89:431–439

    PubMed  CAS  Google Scholar 

  27. Yasuda N, Gotoh K, Minatoguchi S, Asano K, Nishigaki K, Nomura M, Ohno A, Watanabe M, Sano H, Kumada H, Sawa T, Fujiwara H (1998) An increase of soluble Fas, an inhibitor of apoptosis, associated with progression of COPD. Respir Med 92:993–999

    Article  PubMed  CAS  Google Scholar 

  28. Yende S, Waterer GW, Tolley EA, Newman AB, Bauer DC, Taaffe DR, Jensen R, Crapo R, Rubin S, Nevitt M, Simonsick EM, Satterfield S, Harris T, Kritchevsky SB (2006) Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects. Thorax 61:10–16

    Article  PubMed  CAS  Google Scholar 

  29. Van Helvoort HA, Heijdra YF, Thijs HM, Vina J, Wanten GJ, Dekhuijzen PN (2006) Exercise-induced systemic effects in muscle-wasted patients with COPD. Med Sci Sports Exerc 38:1543–1552

    Article  PubMed  CAS  Google Scholar 

  30. Tracey KJ, Cerami A (1990) Metabolic responses to cachectin/TNF. A brief review. Ann NY Acad Sci 587:325–331

    PubMed  CAS  Google Scholar 

  31. Vernooy JH, Kucukaycan M, Jacobs JA, Chavannes NH, Buurman WA, Dentener MA, Wouters EF (2002) Local and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 166:1218–1224

    Article  PubMed  Google Scholar 

  32. Di Francia M, Barbier D, Mege JL, Orehek J (1994) Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 150:1453–1455

    PubMed  CAS  Google Scholar 

  33. De Godoy I, Donahoe M, Calhoun WJ, Mancino J, Rogers RM (1996) Elevated TNF-α production by peripheral blood monocytes of weight-losing COPD patients. Am J Respir Crit Care Med 153:633–637

    PubMed  Google Scholar 

  34. Takabatake N, Nakamura H, Abe S, Inoue S, Hino T, Saito H, Yuki H, Kato S, Tomoike H (2000) The relationship between chronic hypoxemia and activation of tumor necrosis factor-α system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 161:1179–1184

    PubMed  CAS  Google Scholar 

  35. Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C et al (1998) Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 158:1277–1285

    PubMed  CAS  Google Scholar 

  36. Yan SF, Tritto I, Pinsky D, Liao H, Huang J, Fuller G, Brett J, May L, Stern D (1995) Induction of interleukin 6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6. J Biol Chem 270:11463–11471

    Article  PubMed  CAS  Google Scholar 

  37. Rodriguez-Roisin R (2000) Toward a consensus definition for COPD exacerbations. Chest 117(Suppl 2):398s–3401s

    Article  PubMed  CAS  Google Scholar 

  38. Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, Dales RE (2001) Granulocyte airway markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163:349–355

    PubMed  CAS  Google Scholar 

  39. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA (2000) Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 55:114–120

    Article  PubMed  CAS  Google Scholar 

  40. Malo O, Sauleda J, Busquets X, Miralles C, Agusti A, Noguera A (2002) Systemic inflammation during exacerbations of chronic obstructive pulmonary disease. Arch Bronconeumol 38:172–176

    PubMed  CAS  Google Scholar 

  41. Tsoumakidou M, Tzanakis N, Chrysofakis G, Siafakas NM (2005) Nitrosative stress, heme oxygenase-1 expression and airway inflammation during severe exacerbations of COPD. Chest 127:1911–1918

    Article  PubMed  CAS  Google Scholar 

  42. Vestbo J (2006) Clinical assessment, staging, and epidemiology of chronic obstructive pulmonary disease exacerbations. Proc Am Thorac Soc 3:252–256

    Article  PubMed  Google Scholar 

  43. Sin DD, Lacy P, York E, Man SF (2004) Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170:760–765

    Article  PubMed  Google Scholar 

  44. Pinto-Plata VM, Livnat G, Girish M, Cabral H, Masdin P, Linacre P, Dew R, Kenney L, Celli BR (2007) Systemic cytokines, clinical and physiological changes in patients hospitalized for exacerbation of COPD. Chest 131:37–43

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

The study was funded by Adnan Menderes University Research Foundation (Project No. TPF-04027).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fisun Karadag.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karadag, F., Karul, A.B., Cildag, O. et al. Biomarkers of Systemic Inflammation in Stable and Exacerbation Phases of COPD. Lung 186, 403–409 (2008). https://doi.org/10.1007/s00408-008-9106-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-008-9106-6

Keywords

Navigation