COPD pp 129-143 | Cite as

Biomarkers of COPD



Chronic obstructive pulmonary disease (COPD) is a major health burden across the world. Globally, more than 300 million people suffer from COPD [1] and nearly three million die each year from this disease [2]. COPD mortality continues to climb at an alarming rate, such that by 2030, nearly nine million people will die annually from COPD [3]. The economic burden of COPD is also enormous. In the United States alone, COPD accounted for $20.9 billion USD in direct and $7.4 billion USD in indirect costs in 2004 [4]. Regrettably, the pipeline for new drugs for COPD is relatively dry compared to other major causes of mortality such as HIV/AIDs, cancer, and diabetes [5]. One major barrier to drug discovery in COPD is the paucity of well-accepted and well-validated biomarkers. Currently, the only “marker” that is widely accepted by regulatory agencies for new drug approval in COPD is FEV1 (forced expiratory volume in 1 s), which is a robust measure of lung function. However, COPD is defined operationally as a chronic respiratory condition that results in airflow limitation which is progressive and not fully reversible [6]. In other words, COPD is defined by limited reversibility of FEV1, making this endpoint unsuitable for drug discovery in COPD. The discovery of a validated, reliable, robust, and reproducible blood biomarker would provide a major boost to the development of novel compounds because it would allow investigators (and companies) to demonstrate the therapeutic promise of a drug in small (usually phase II) trials before proceeding to a much more expensive and logistically difficult phase III trials. Without such data, pharmaceutical companies are hesitant to invest millions of dollars on large phase III studies to bring compounds to market. For this reason, some international companies have recently abandoned COPD drug development altogether, while many others have scaled back their efforts significantly. The purpose of this chapter is to review potential biomarkers of COPD, especially those that could be used in predicting treatment responses.


  1. 1.
    Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM, et al. International variation in the prevalence of COPD (the BOLD study): a population-based prevalence study. Lancet. 2007;370(9589):741–50.PubMedCrossRefGoogle Scholar
  2. 2.
    Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: global burden of disease study. Lancet. 1997;349(9064):1498–504.PubMedCrossRefGoogle Scholar
  3. 3.
    Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    National Heart L, and Blood Institute. Morbidity and mortality: chartbook on cardiovascular, lung, and blood diseases. In: US Department of Health and Human Services PHS, editor. National Institutes of Health; 2004.Google Scholar
  5. 5.
    Sin DD, Man SF. Steroids in COPD: still up in the air? Eur Respir J. 2010;35(5):949–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532–55.PubMedCrossRefGoogle Scholar
  7. 7.
    Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;364(9435):709–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Dragonieri S, Tongoussouva O, Zanini A, Imperatori A, Spanevello A. Markers of airway inflammation in pulmonary diseases assessed by induced sputum. Monaldi Arch Chest Dis. 2009;71(3):119–26.PubMedGoogle Scholar
  9. 9.
    Borrill ZL, Roy K, Singh D. Exhaled breath condensate biomarkers in COPD. Eur Respir J. 2008;32(2):472–86.PubMedCrossRefGoogle Scholar
  10. 10.
    He ZY, Ou LM, Zhang JQ, Bai J, Liu GN, Li MH, et al. Effect of 6 months of erythromycin treatment on inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease. Respiration. 2010;80(6):445–52.PubMedCrossRefGoogle Scholar
  11. 11.
    Comandini A, Rogliani P, Nunziata A, Cazzola M, Curradi G, Saltini C. Biomarkers of lung damage associated with tobacco smoke in induced sputum. Respir Med. 2009;103(11):1592–613.PubMedCrossRefGoogle Scholar
  12. 12.
    Cazzola M, Novelli G. Biomarkers in COPD. Pulm Pharmacol Ther. 23(6):493–500.Google Scholar
  13. 13.
    Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ. Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest. 2010;137(6):1338–44.PubMedCrossRefGoogle Scholar
  14. 14.
    Sharafkhaneh A, Hanania NA, Kim V. Pathogenesis of emphysema: from the bench to the bedside. Proc Am Thorac Soc. 2008;5(4):475–7.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Cowburn AS, Condliffe AM, Farahi N, Summers C, Chilvers ER. Advances in neutrophil biology. Chest. 2008;134(3):606–12.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    O'Donnell RA, Peebles C, Ward JA, Daraker A, Angco G, Broberg P, et al. Relationship between peripheral airway dysfunction, airway obstruction, and neutrophilic inflammation in COPD. Thorax. 2004;59(10):837–42.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    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;153(2):530–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Williams TJ, Jose PJ. Neutrophils in chronic obstructive pulmonary disease. Novartis Found Symp. 2001;234:136–41, discussion 41–8.Google Scholar
  19. 19.
    Perng DW, Huang HY, Chen HM, Lee YC, Perng RP. Characteristics of airway inflammation and bronchodilator reversibility in COPD: a potential guide to treatment. Chest. 2004;126(2):375–81.PubMedCrossRefGoogle Scholar
  20. 20.
    Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W. Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J. 2005;26(5):835–45.PubMedCrossRefGoogle Scholar
  21. 21.
    Stanescu D, Sanna A, Veriter C, Kostianev S, Calcagni PG, Fabbri LM, et al. Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils. Thorax. 1996;51(3):267–71.Google Scholar
  22. 22.
    Barnes NC, Qiu YS, Pavord ID, Parker D, Davis PA, Zhu J, et al. Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease. Am J Respir Crit Care Med. 2006;173(7):736–43.PubMedCrossRefGoogle Scholar
  23. 23.
    Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med. 2008;178(4):332–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Lapperre TS, Snoeck-Stroband JB, Gosman MM, Jansen DF, van Schadewijk A, Thiadens HA, et al. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2009;151(8):517–27.PubMedCrossRefGoogle Scholar
  25. 25.
    Gan WQ, Man SF, Sin DD. Effects of inhaled corticosteroids on sputum cell counts in stable chronic obstructive pulmonary disease: a systematic review and a meta-analysis. BMC Pulm Med. 2005;5:3.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kanehara M, Yokoyama A, Tomoda Y, Shiota N, Iwamoto H, Ishikawa N, et al. Anti-inflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2008;21(6):874–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Gronke L, Beeh KM, Cameron R, Kornmann O, Beier J, Shaw M, et al. Effect of the oral leukotriene B4 receptor antagonist LTB019 on inflammatory sputum markers in patients with chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2008;21(2):409–17.PubMedCrossRefGoogle Scholar
  28. 28.
    Singh D, Edwards L, Tal-Singer R, Rennard S. Sputum neutrophils as a biomarker in COPD: findings from the ECLIPSE study. Respir Res. 11(1):77.Google Scholar
  29. 29.
    Boorsma M, Lutter R, van de Pol MA, Out TA, Jansen HM, Jonkers RE. Long-term effects of budesonide on inflammatory status in COPD. COPD. 2008;5(2):97–104.PubMedCrossRefGoogle Scholar
  30. 30.
    Kharitonov SA, Barnes PJ. Exhaled biomarkers. Chest. 2006;130(5):1541–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Barnes PJ, Dweik RA, Gelb AF, Gibson PG, George SC, Grasemann H, et al. Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest. 2010;138(3):682–92.PubMedCrossRefGoogle Scholar
  32. 32.
    Dupont LJ, Demedts MG, Verleden GM. Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma*. Chest. 2003;123(3):751–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Van Den Toorn LM, Overbeek SE, De Jongste JC, Leman K, Hoogsteden HC, Prins J-B. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med. 2001;164(11):2107–13.PubMedCrossRefGoogle Scholar
  34. 34.
    Kharitonov SA, Donnelly LE, Montuschi P, Corradi M, Collins JV, Barnes PJ. Dose-dependent onset and cessation of action of inhaled budesonide on exhaled nitric oxide and symptoms in mild asthma. Thorax. 2002;57(10):889–96.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Jones SL, Kittelson J, Cowan JO, Flannery EM, Hancox RJ, McLachlan CR, et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med. 2001;164(5):738–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med. 2001;163(7):1693–722.PubMedCrossRefGoogle Scholar
  37. 37.
    Verleden GM, Dupont LJ, Verpeut AC, Demedts MG. The effect of cigarette smoking on exhaled nitric oxide in mild steroid-naive asthmatics*. Chest. 1999;116(1):59–64.PubMedCrossRefGoogle Scholar
  38. 38.
    Kharitonov SA, Robbins RA, Yates D, Keatings V, Barnes PJ. Acute and chronic effects of cigarette smoking on exhaled nitric oxide. Am J Respir Crit Care Med. 1995;152(2):609–12.PubMedCrossRefGoogle Scholar
  39. 39.
    Brindicci C, Ito K, Resta O, Pride NB, Barnes PJ, Kharitonov SA. Exhaled nitric oxide from lung periphery is increased in COPD. Eur Respir J. 2005;26(1):52–9.PubMedCrossRefGoogle Scholar
  40. 40.
    MacNee W, Rennard SI, Hunt JF, Edwards LD, Miller BE, Locantore NW, et al. Evaluation of exhaled breath condensate pH as a biomarker for COPD. Respir Med. 2011;105(7):1037–45.PubMedCrossRefGoogle Scholar
  41. 41.
    Biernacki WA, Kharitonov SA, Barnes PJ. Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD. Thorax. 2003;58(4):294–8.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Corhay J-L, Henket M, Nguyen D, Duysinx B, Sele J, Louis R. Leukotriene B4 contributes to exhaled breath condensate and sputum neutrophil Chemotaxis in COPD. Chest. 2009;136(4):1047–54.PubMedCrossRefGoogle Scholar
  43. 43.
    Mercken EM, Gosker HR, Rutten EP, Wouters EF, Bast A, Hageman GJ, et al. Systemic and pulmonary oxidative stress after single-leg exercise in COPD. Chest. 2009;136(5):1291–300.PubMedCrossRefGoogle Scholar
  44. 44.
    Shifren A, Mecham RP. The stumbling block in lung repair of emphysema: elastic fiber assembly. Proc Am Thorac Soc. 2006;3(5):428–33.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Pelosi P, Rocco PR. Effects of mechanical ventilation on the extracellular matrix. Intensive Care Med. 2008;34(4):631–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Abraham T, Hogg J. Extracellular matrix remodeling of lung alveolar walls in three dimensional space identified using second harmonic generation and multiphoton excitation fluorescence. J Struct Biol. 2010;171(2):189–96.PubMedCrossRefGoogle Scholar
  47. 47.
    Kelleher CM, Silverman EK, Broekelmann T, Litonjua AA, Hernandez M, Sylvia JS, et al. A functional mutation in the terminal exon of elastin in severe, early-onset chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2005;33(4):355–62.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Wendel DP, Taylor DG, Albertine KH, Keating MT, Li DY. Impaired distal airway development in mice lacking elastin. Am J Respir Cell Mol Biol. 2000;23(3):320–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Luisetti M, Ma S, Iadarola P, Stone PJ, Viglio S, Casado B, et al. Desmosine as a biomarker of elastin degradation in COPD: current status and future directions. Eur Respir J. 2008;32(5):1146–57.PubMedCrossRefGoogle Scholar
  50. 50.
    Rosenbloom J. Biochemical/immunologic markers of emphysema. Ann N Y Acad Sci. 1991;624:7–12.PubMedCrossRefGoogle Scholar
  51. 51.
    Goldstein RA, Starcher BC. Urinary excretion of elastin peptides containing desmosin after intratracheal injection of elastase in hamsters. J Clin Invest. 1978;61(5):1286–90.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Churg A, Dai J, Tai H, Xie C, Wright JL. Tumor necrosis factor-alpha is central to acute cigarette smoke-induced inflammation and connective tissue breakdown. Am J Respir Crit Care Med. 2002;166(6):849–54.PubMedCrossRefGoogle Scholar
  53. 53.
    Churg A, Wang RD, Tai H, Wang X, Xie C, Wright JL. Tumor necrosis factor-alpha drives 70% of cigarette smoke-induced emphysema in the mouse. Am J Respir Crit Care Med. 2004;170(5):492–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Huang JT-J, Chaudhuri R, Albarbarawi O, Barton A, Grierson C, Rauchhaus P, et al. Clinical validity of plasma and urinary desmosine as biomarkers for chronic obstructive pulmonary disease. Thorax. 2012;67(6):502–8.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Rabinovich RA, Miller BE, Wrobel K, Ranjit K, Williams MC, Drost E, et al. Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD. Eur Respir J. 2016;47(5):1365–73.PubMedCrossRefGoogle Scholar
  56. 56.
    Fiorenza D, Viglio S, Lupi A, Baccheschi J, Tinelli C, Trisolini R, et al. Urinary desmosine excretion in acute exacerbations of COPD: a preliminary report. Respir Med. 2002;96(2):110–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Ma S, Lin YY, Turino GM. Measurements of desmosine and isodesmosine by mass spectrometry in COPD*. Chest. 2007;131(5):1363–71.PubMedCrossRefGoogle Scholar
  58. 58.
    Cocci F, Miniati M, Monti S, Cavarra E, Gambelli F, Battolla L, et al. Urinary desmosine excretion is inversely correlated with the extent of emphysema in patients with chronic obstructive pulmonary disease. Int J Biochem Cell Biol. 2002;34(6):594–604.PubMedCrossRefGoogle Scholar
  59. 59.
    Stone PJ, Morris TA 3rd, Franzblau C, Snider GL. Preliminary evidence that augmentation therapy diminishes degradation of cross-linked elastin in alpha-1-antitrypsin-deficient humans. Respiration. 1995;62(2):76–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Gottlieb DJ, Luisetti M, Stone PJ, Allegra L, Cantey-Kiser JM, Grassi C, et al. Short-term supplementation therapy does not affect elastin degradation in severe alpha(1)-antitrypsin deficiency. The American-Italian AATD study group. Am J Respir Crit Care Med. 2000;162(6):2069–72.PubMedCrossRefGoogle Scholar
  61. 61.
    Ma S, Lin Y, Tartell L, Turino G. The effect of tiotropium therapy on markers of elastin degradation in COPD. Respir Res. 2009;10(1):12.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Dahl R, Titlestad I, Lindqvist A, Wielders P, Wray H, Wang M, et al. Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial. Pulm Pharmacol Ther. 2012;25(2):169–77.PubMedCrossRefGoogle Scholar
  63. 63.
    Weathington NM, van Houwelingen AH, Noerager BD, Jackson PL, Kraneveld AD, Galin FS, et al. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat Med. 2006;12(3):317–23.PubMedCrossRefGoogle Scholar
  64. 64.
    Gaggar A, Jackson PL, Noerager BD, O’Reilly PJ, McQuaid DB, Rowe SM, et al. A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation. J Immunol. 2008;180(8):5662–9.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Laskin DL, Kimura T, Sakakibara S, Riley DJ, Berg RA. Chemotactic activity of collagen-like polypeptides for human peripheral blood neutrophils. J Leukoc Biol. 1986;39(3):255–66.PubMedGoogle Scholar
  66. 66.
    Postlethwaite AE, Kang AH. Collagen-and collagen peptide-induced chemotaxis of human blood monocytes. J Exp Med. 1976;143(6):1299–307.PubMedCrossRefGoogle Scholar
  67. 67.
    Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley DG, Marconcini LA, et al. Elastin fragments drive disease progression in a murine model of emphysema. J Clin Invest. 2006;116(3):753–9.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    van Houwelingen AH, Weathington NM, Verweij V, Blalock JE, Nijkamp FP, Folkerts G. Induction of lung emphysema is prevented by L-arginine-threonine-arginine. FASEB J. 2008;22(9):3403–8.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    O’Reilly P, Jackson PL, Noerager B, Parker S, Dransfield M, Gaggar A, et al. N-alpha-PGP and PGP, potential biomarkers and therapeutic targets for COPD. Respir Res. 2009;10:38.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    O’Reilly PJ, Jackson PL, Wells JM, Dransfield MT, Scanlon PD, Blalock JE. Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations. BMJ Open. 2013;3(12):e004140.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Wells JM, Jackson PL, Viera L, Bhatt SP, Gautney J, Handley G, et al. A randomized, placebo-controlled trial of Roflumilast. Effect on proline-glycine-proline and neutrophilic inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(8):934–42.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Snelgrove RJ, Jackson PL, Hardison MT, Noerager BD, Kinloch A, Gaggar A, et al. A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science. 330(6000):90–4.Google Scholar
  73. 73.
    van Eeden SF, Sin DD. Chronic obstructive pulmonary disease: a chronic systemic inflammatory disease. Respiration. 2008;75(2):224–38.PubMedCrossRefGoogle Scholar
  74. 74.
    Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;279(18):1477–82.PubMedCrossRefGoogle Scholar
  75. 75.
    Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132–40.PubMedCrossRefGoogle Scholar
  76. 76.
    Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.PubMedCrossRefGoogle Scholar
  77. 77.
    Karadag F, Kirdar S, Karul AB, Ceylan E. The value of C-reactive protein as a marker of systemic inflammation in stable chronic obstructive pulmonary disease. Eur J Intern Med. 2008;19(2):104–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Garrod R, Marshall J, Barley E, Fredericks S, Hagan G. The relationship between inflammatory markers and disability in chronic obstructive pulmonary disease (COPD). Prim Care Respir J. 2007;16(4):236–40.PubMedCrossRefGoogle Scholar
  79. 79.
    Man SFP, Connett JE, Anthonisen NR, Wise RA, Tashkin DP, Sin DD. C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease. Thorax. 2006;61(10):849–53.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(3):250–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(10):982–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Hurst JR, Donaldson GC, Perera WR, Wilkinson TMA, Bilello JA, Hagan GW, et al. Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;174(8):867–74.PubMedCrossRefGoogle Scholar
  83. 83.
    Sin DD, Lacy P, York E, Man SFP. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170(7):760–5.PubMedCrossRefGoogle Scholar
  84. 84.
    Perng DW, Tao CW, Su KC, Tsai CC, Liu LY, Lee YC. Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD. Eur Respir J. 2009;33(4):778–84.PubMedCrossRefGoogle Scholar
  85. 85.
    Sin DD, Man SF, Marciniuk DD, Ford G, FitzGerald M, Wong E, et al. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177(11):1207–14.PubMedCrossRefGoogle Scholar
  86. 86.
    Fibrinogen SC. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality. JAMA. 2005;294(14):1799–809.Google Scholar
  87. 87.
    Groenewegen KH, Postma DS, Hop WCJ, Wielders PLML, Schölsser NJ, Wouters EF. Increased systemic inflammation is a risk factor for COPD exacerbations*. Chest. 2008;133(2):350–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Engstrom G, Segelstorm N, Ekberg-Aronsson M, Nilsson PM, Lindgarde F, Lofdahl CG. Plasma markers of inflammation and incidence of hospitalisations for COPD: results from a population-based cohort study. Thorax. 2009;64(3):211–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Duvoix A, Dickens J, Haq I, Mannino D, Miller B, Tal-Singer R, et al. Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. Thorax. 2013;68(7):670–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Valvi D, Mannino DM, Müllerova H, Tal-Singer R. Fibrinogen, chronic obstructive pulmonary disease (COPD) and outcomes in two United States cohorts. Int J COPD. 2012;7:173–82.Google Scholar
  91. 91.
    Dentener MA, Creutzberg EC, Pennings HJ, Rijkers GT, Mercken E, Wouters EF. Effect of infliximab on local and systemic inflammation in chronic obstructive pulmonary disease: a pilot study. Respiration. 2008;76(3):275–82.PubMedCrossRefGoogle Scholar
  92. 92.
    Kaczmarek P, Sladek K, Skucha W, Rzeszutko M, Iwaniec T, Dziedzina S, et al. The influence of simvastatin on selected inflammatory markers in patients with chronic obstructive pulmonary disease. Pol Arch Med Wewn. 2010;120(1–2):11–7.PubMedGoogle Scholar
  93. 93.
    Kishimoto T. IL-6: from its discovery to clinical applications. Int Immunol. 2010;22(5):347–52.PubMedCrossRefGoogle Scholar
  94. 94.
    Ishii H, Hayashi S, Hogg JC, Fujii T, Goto Y, Sakamoto N, et al. Alveolar macrophage-epithelial cell interaction following exposure to atmospheric particles induces the release of mediators involved in monocyte mobilization and recruitment. Respir Res. 2005;6:87.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kido T, Tamagawa E, Bai N, Suda K, Yang HH, Li Y, et al. Particulate matter induces translocation of IL-6 from the lung to the systemic circulation. Am J Respir Cell Mol Biol. 2011;44(2):197–204.PubMedCrossRefGoogle Scholar
  96. 96.
    Thorleifsson SJ, Margretardottir OB, Gudmundsson G, Olafsson I, Benediktsdottir B, Janson C, et al. Chronic airflow obstruction and markers of systemic inflammation: results from the BOLD study in Iceland. Respir Med. 2009;103(10):1548–53.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Walter RE, Wilk JB, Larson MG, Vasan RS, Keaney JF Jr, Lipinska I, et al. Systemic inflammation and COPD: the Framingham heart study. Chest. 2008;133(1):19–25.PubMedCrossRefGoogle Scholar
  98. 98.
    Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1065–72.PubMedCrossRefGoogle Scholar
  99. 99.
    Bozinovski S, Hutchinson A, Thompson M, MacGregor L, Black J, Giannakis E, et al. Serum amyloid a is a biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177(3):269–78.PubMedCrossRefGoogle Scholar
  100. 100.
    Koutsokera A, Kiropoulos TS, Nikoulis DJ, Daniil ZD, Tsolaki V, Tanou K, et al. Clinical, functional and biochemical changes during recovery from COPD exacerbations. Respir Med. 2009;103(6):919–26.PubMedCrossRefGoogle Scholar
  101. 101.
    Cole FS. Surfactant protein B: unambiguously necessary for adult pulmonary function. Am J Physiol Lung Cell Mol Physiol. 2003;285(3):L540–L2.PubMedCrossRefGoogle Scholar
  102. 102.
    Hartl D, Griese M. Surfactant protein D in human lung diseases. Eur J Clin Invest. 2006;36(6):423–35.PubMedCrossRefGoogle Scholar
  103. 103.
    Sin DD, Pahlavan PS, Man SFP. Review: surfactant protein D: a lung specific biomarker in COPD? Ther Adv Respir Dis. 2008;2(2):65–74.PubMedCrossRefGoogle Scholar
  104. 104.
    Kishore U, Greenhough TJ, Waters P, Shrive AK, Ghai R, Kamran MF, et al. Surfactant proteins SP-A and SP-D: structure, function and receptors. Mol Immunol. 2006;43(9):1293–315.PubMedCrossRefGoogle Scholar
  105. 105.
    Crouch EC. Surfactant protein-D and pulmonary host defense. Respir Res. 2000;1(2):93–108.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Guo CJ, Atochina-Vasserman EN, Abramova E, Foley JP, Zaman A, Crouch E, et al. S-nitrosylation of surfactant protein-D controls inflammatory function. PLoS Biol. 2008;6(11):e266.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    More JM, Voelker DR, Silveira LJ, Edwards MG, Chan ED, Bowler RP. Smoking reduces surfactant protein D and phospholipids in patients with and without chronic obstructive pulmonary disease. BMC Pulm Med. 2010;10:53.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Honda Y, Takahashi H, Kuroki Y, Akino T, Abe S. Decreased contents of surfactant proteins a and D in BAL fluids of healthy smokers. Chest. 1996;109(4):1006–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Lomas DA, Silverman EK, Edwards LD, Locantore NW, Miller BE, Horstman DH, et al. Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD. Eur Respir J. 2009;34(1):95–102.PubMedCrossRefGoogle Scholar
  110. 110.
    Tkacova R, McWilliams A, Lam S, Sin DD. Integrating lung and plasma expression of pneumo-proteins in developing biomarkers in COPD: a case study of surfactant protein D. Med Sci Monit. 2010;16(11):CR540–4.PubMedGoogle Scholar
  111. 111.
    Shakoori TA, Sin DD, Ghafoor F, Bashir S, Bokhari SN. Serum surfactant protein D during acute exacerbations of chronic obstructive pulmonary disease. Dis Markers. 2009;27(6):287–94.PubMedCrossRefGoogle Scholar
  112. 112.
    Hurst JR, Vestbo J, Anzueto A, Locantore N, Mullerova H, Tal-Singer R, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128–38.PubMedCrossRefGoogle Scholar
  113. 113.
    Umland TC, Swaminathan S, Singh G, Warty V, Furey W, Pletcher J, et al. Structure of a human Clara cell phospholipid-binding protein-ligand complex at 1.9 A resolution. Nat Struct Biol. 1994;1(8):538–45.PubMedCrossRefGoogle Scholar
  114. 114.
    Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy. 2000;30(4):469–75.PubMedCrossRefGoogle Scholar
  115. 115.
    Yoneda K. Ultrastructural localization of phospholipases in the Clara cell of the rat bronchiole. Am J Pathol. 1978;93(3):745–52.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Lakind JS, Holgate ST, Ownby DR, Mansur AH, Helms PJ, Pyatt D, et al. A critical review of the use of Clara cell secretory protein (CC16) as a biomarker of acute or chronic pulmonary effects. Biomarkers. 2007;12(5):445–67.PubMedCrossRefGoogle Scholar
  117. 117.
    Alexis NE, Lay JC, Haczku A, Gong H, Linn W, Hazucha MJ, et al. Fluticasone propionate protects against ozone-induced airway inflammation and modified immune cell activation markers in healthy volunteers. Environ Health Perspect. 2008;116(6):799–805.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Shijubo N, Itoh Y, Yamaguchi T, Shibuya Y, Morita Y, Hirasawa M, et al. Serum and BAL Clara cell 10 kDa protein (CC10) levels and CC10-positive bronchiolar cells are decreased in smokers. Eur Respir J. 1997;10(5):1108–14.PubMedCrossRefGoogle Scholar
  119. 119.
    Shijubo N, Itoh Y, Yamaguchi T, Imada A, Hirasawa M, Yamada T, et al. Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med. 1999;160(3):930–3.PubMedCrossRefGoogle Scholar
  120. 120.
    Mattsson J, Remberger M, Andersson O, Sundberg B, Nord M. Decreased serum levels of clara cell secretory protein (CC16) are associated with bronchiolitis obliterans and may permit early diagnosis in patients after allogeneic stem-cell transplantation. Transplantation. 2005;79(10):1411–6.PubMedCrossRefGoogle Scholar
  121. 121.
    Tsoumakidou M, Bouloukaki I, Thimaki K, Tzanakis N, Siafakas NM. Innate immunity proteins in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Exp Lung Res. 2010;36(6):373–80.PubMedCrossRefGoogle Scholar
  122. 122.
    Lomas DA, Silverman EK, Edwards LD, Miller BE, Coxson HO, Tal-Singer R, et al. Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort. Thorax. 2008;63(12):1058–63.PubMedCrossRefGoogle Scholar
  123. 123.
    Günther C, Bello-Fernandez C, Kopp T, Kund J, Carballido-Perrig N, Hinteregger S, et al. CCL18 is expressed in atopic dermatitis and mediates skin homing of human memory T cells. J Immunol. 2005;174(3):1723–8.PubMedCrossRefGoogle Scholar
  124. 124.
    Prasse A, Probst C, Bargagli E, Zissel G, Toews GB, Flaherty KR, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179(8):717–23.PubMedCrossRefGoogle Scholar
  125. 125.
    Prasse A, Pechkovsky DV, Toews GB, Schäfer M, Eggeling S, Ludwig C, et al. CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum. 2007;56(5):1685–93.PubMedCrossRefGoogle Scholar
  126. 126.
    Kraaijeveld AO, de Jager SCA, de Jager WJ, Prakken BJ, McColl SR, Haspels I, et al. CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischemic symptoms. Circulation. 2007;116(17):1931–41.PubMedCrossRefGoogle Scholar
  127. 127.
    Sin DD, Miller B, Duvoix A, Man SFP, Zhang X, Silverman EK, et al. Serum PARC/CCL-18 concentrations and health outcomes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;183(9):1187–92.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Man SF, Xuekui Z, Vessey R, Walker T, Lee K, Park D, et al. The effects of inhaled and oral corticosteroids on serum inflammatory biomarkers in COPD: an exploratory study. Ther Adv Respir Dis. 2009;3(2):73–80.PubMedCrossRefGoogle Scholar
  129. 129.
    Donaldson GC, Seemungal TAR, Patel IS, Bhowmik A, Wilkinson TMA, Hurst JR, et al. Airway and systemic inflammation and decline in lung function in patients with COPD*. Chest. 2005;128(4):1995–2004.PubMedCrossRefGoogle Scholar
  130. 130.
    Karadag F, Karul A, Cildag O, Yilmaz M, Ozcan H. Biomarkers of systemic inflammation in stable and exacerbation phases of COPD. Lung. 2008;186(6):403–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Toedter G, Li K, Marano C, Ma K, Sague S, Huang CC, et al. Gene expression profiling and response signatures associated with differential responses to infliximab treatment in ulcerative colitis. Am J Gastroenterol. 2011;106(7):1272–80.PubMedCrossRefGoogle Scholar
  132. 132.
    Elashoff MR, Wingrove JA, Beineke P, Daniels SE, Tingley WG, Rosenberg S, et al. Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in non-diabetic patients. BMC Med Genet. 2011;4(1):26.Google Scholar
  133. 133.
    Bhattacharya S, Srisuma S, DeMeo DL, Shapiro SD, Bueno R, Silverman EK, et al. Molecular biomarkers for quantitative and discrete COPD phenotypes. Am J Respir Cell Mol Biol. 2009;40(3):359–67.PubMedCrossRefGoogle Scholar
  134. 134.
    Silverman EK, Spira A, Pare PD. Genetics and genomics of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;6(6):539–42.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Aronson D, Roterman I, Yigla M, Kerner A, Avizohar O, Sella R, et al. Inverse association between pulmonary function and C-reactive protein in apparently healthy subjects. Am J Respir Crit Care Med. 2006;174(6):626–32.PubMedCrossRefGoogle Scholar
  136. 136.
    Cosio BG, Iglesias A, Rios A, Noguera A, Sala E, Ito K, et al. Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD. Thorax. 2009;64(5):424–9.PubMedCrossRefGoogle Scholar
  137. 137.
    Dahl M, Tybjoerg-Hansen A, Vestbo J, Lange P, Nordestgaard BG. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(6):1008–11.PubMedCrossRefGoogle Scholar
  138. 138.
    Wedzicha JA, Seemungal TA, MacCallum PK, Paul EA, Donaldson GC, Bhowmik A, et al. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. Thromb Haemost. 2000;84(2):210–5.PubMedGoogle Scholar
  139. 139.
    Tkacova R, McWilliams A, Lam S, Sin DD. Integrating lung and plasma expression of pneumo-proteins in developing biomarkers in COPD: a case study of surfactant protein D. Med Sci Monit. 16(11):CR540–4.Google Scholar
  140. 140.
    Pinto-Plata V, Toso J, Lee K, Park D, Bilello J, Mullerova H, et al. Profiling serum biomarkers in patients with COPD: associations with clinical parameters. Thorax. 2007;62(7):595–601.PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Seoul National University Bundang HospitalSeongnamSouth Korea

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