Anti-Inflammatory Therapeutics in COPD: Past, Present, and Future

Chapter

Abstract

Corticosteroids are highly effective in the therapy of asthma; whereas they have little or no anti-inflammatory effects in most patients with COPD. This has prompted a search for alternative anti-inflammatory treatments, and this has so far proved to be a great challenge. The only effective anti- inflammatory treatment for COPD that is in current use is theophylline, which is widely used in developing countries but little use in Western countries because of its side effects at high doses. There is a pressing need to develop new anti-inflammatory treatments in order to more effectively treat systems, prevent exacerbations, reduce disease progression, and reduce mortality.

Keywords

Osteoporosis Corticosteroid Ozone Pneumonia Adenosine 

References

  1. 1.
    Hogg JC (2004) Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 364(9435):709–721PubMedGoogle Scholar
  2. 2.
    McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG et al (2011) Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med 365(17):1567–1575PubMedGoogle Scholar
  3. 3.
    Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L et al (2004) The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 350(26): 2645–2653PubMedGoogle Scholar
  4. 4.
    Barnes PJ (2008) Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 8:183–192PubMedGoogle Scholar
  5. 5.
    Barnes PJ, Shapiro SD, Pauwels RA (2003) Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 22(4):672–688PubMedGoogle Scholar
  6. 6.
    Brusselle GG, Joos GF, Bracke KR (2011) New insights into the immunology of chronic obstructive pulmonary disease. Lancet 378(9795):1015–1026PubMedGoogle Scholar
  7. 7.
    Cosio MG, Saetta M, Agusti A (2009) Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 360(23):2445–2454PubMedGoogle Scholar
  8. 8.
    Barnes PJ (2008) Cytokine networks in asthma and chronic obstructive pulmonary disease. J Clin Invest 118:3546–3556PubMedGoogle Scholar
  9. 9.
    Barnes PJ (2009) The cytokine network in COPD. Am J Respir Cell Mol Biol 41:631–638PubMedGoogle Scholar
  10. 10.
    Bowler RP, Barnes PJ, Crapo JD (2004) The role of oxidative stress in chronic obstructive pulmonary disease. J COPD 2:255–277Google Scholar
  11. 11.
    Barnes PJ, Celli BR (2009) Systemic manifestations and comorbidities of COPD. Eur Respir J 33(5):1165–1185PubMedGoogle Scholar
  12. 12.
    Celli BR, Barnes PJ (2007) Exacerbations of chronic obstructive pulmonary disease. Eur Respir J 29(6):1224–1238PubMedGoogle Scholar
  13. 13.
    Hurst JR, Vestbo J, Anzueto A, Locantore N, Mullerova H, Tal-Singer R et al (2010) Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 363(12):1128–1138PubMedGoogle Scholar
  14. 14.
    Taylor AE, Finney-Hayward TK, Quint JK, Thomas CM, Tudhope SJ, Wedzicha JA et al (2010) Defective macrophage phagocytosis of bacteria in COPD. Eur Respir J 35:1039–1047PubMedGoogle Scholar
  15. 15.
    Wessler I, Kirkpatrick CJ (2008) Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 154(8):1558–1571PubMedGoogle Scholar
  16. 16.
    Koarai A, Traves SL, Fenwick PS, Brown SM, Chana KK, Russell RE et al (2011) Expression of muscarinic receptors by human macrophages. Eur Respir J 39(3):698–704PubMedGoogle Scholar
  17. 17.
    Powrie DJ, Wilkinson TM, Donaldson GC, Jones P, Scrine K, Viel K et al (2007) Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J 30(3):472–478PubMedGoogle Scholar
  18. 18.
    Donnelly LE, Tudhope SJ, Fenwick PS, Barnes PJ (2009) Effects of formoterol and salmeterol on cytokine release from monocyte-derived macrophages. Eur Respir J 36(1):178–186PubMedGoogle Scholar
  19. 19.
    Barnes PJ (2010) Inhaled corticosteroids in COPD: a controversy. Respiration 80:89–95PubMedGoogle Scholar
  20. 20.
    Barnes PJ (2000) Inhaled corticosteroids are not helpful in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 161:342–344PubMedGoogle Scholar
  21. 21.
    Suissa S, Barnes PJ (2009) Inhaled corticosteroids in COPD: the case against. Eur Respir J 34(1):13–16PubMedGoogle Scholar
  22. 22.
    Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P et al (2007) Global strategy for the diagnosis, management, and prevention of COPD – 2006 Update. Am J Respir Crit Care Med 176:532–555PubMedGoogle Scholar
  23. 23.
    Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K (1999) Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 353(9167):1819–1823PubMedGoogle Scholar
  24. 24.
    Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB et al (1999) Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 340(25):1948–1953PubMedGoogle Scholar
  25. 25.
    Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen T (2000) Randomised, double-blind, placebo-controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease; the ISOLDE trial. Br Med J 320:1297–1303Google Scholar
  26. 26.
    Lung Health Study Research Group (2000) Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 343(26):1902–1909Google Scholar
  27. 27.
    Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimou J (1998) Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 351:773–780PubMedGoogle Scholar
  28. 28.
    Highland KB, Strange C, Heffner JE (2003) Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med 138(12):969–973PubMedGoogle Scholar
  29. 29.
    Sin DD, Wu L, Anderson JA, Anthonisen NR, Buist AS, Burge PS et al (2005) Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax 60(12):992–997PubMedGoogle Scholar
  30. 30.
    Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW et al (2007) Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 356(8):775–789PubMedGoogle Scholar
  31. 31.
    Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW et al (2008) 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 178(4):332–338PubMedGoogle Scholar
  32. 32.
    Yang IA, Fong KM, Sim EH, Black PN, Lasserson TJ (2007) Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2:CD002991PubMedGoogle Scholar
  33. 33.
    Suissa S, Ernst P, Vandemheen KL, Aaron SD (2008) Methodological issues in therapeutic trials of COPD. Eur Respir J 31(5):927–933PubMedGoogle Scholar
  34. 34.
    Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R et al (2007) Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 146(8):545–555PubMedGoogle Scholar
  35. 35.
    Suissa S (2008) Lung function decline in COPD trials: bias from regression to the mean. Eur Respir J 32(4):829–831PubMedGoogle Scholar
  36. 36.
    Suissa S (2008) Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 167(4): 492–499PubMedGoogle Scholar
  37. 37.
    Suissa S (2006) Observational studies of inhaled corticosteroids in chronic obstructive pulmonary disease: misconstrued immortal time bias. Am J Respir Crit Care Med 173(4): 464–465PubMedGoogle Scholar
  38. 38.
    Papi A, Romagnoli M, Baraldo S, Braccioni F, Guzzinati I, Saetta M et al (2000) Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 162(5):1773–1777PubMedGoogle Scholar
  39. 39.
    Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ et al (2000) Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 356(9240):1480–1485PubMedGoogle Scholar
  40. 40.
    Siva R, Green RH, Brightling CE, Shelley M, Hargadon B, McKenna S et al (2007) Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J 29(5):906–913PubMedGoogle Scholar
  41. 41.
    Ernst P, Baltzan M, Deschenes J, Suissa S (2006) Low-dose inhaled and nasal corticosteroid use and the risk of cataracts. Eur Respir J 27(6):1168–1174PubMedGoogle Scholar
  42. 42.
    Hubbard R, Tattersfield A, Smith C, West J, Smeeth L, Fletcher A (2006) Use of inhaled corticosteroids and the risk of fracture. Chest 130(4):1082–1088PubMedGoogle Scholar
  43. 43.
    Graat-Verboom L, Wouters EF, Smeenk FW, van den Borne BE, Lunde R, Spruit MA (2009) Current status of research on osteoporosis in COPD: a systematic review. Eur Respir J 34(1):209–218PubMedGoogle Scholar
  44. 44.
    Scanlon PD, Connett JE, Wise RA, Tashkin DP, Madhok T, Skeans M et al (2004) Loss of bone density with inhaled triamcinolone in lung health study II. Am J Respir Crit Care Med 170(12):1302–1309PubMedGoogle Scholar
  45. 45.
    Ferguson GT, Calverley PM, Anderson JA, Jenkins CR, Jones PW, Willits LR et al (2009) Prevalence and progression of osteoporosis in patients with COPD. Results from TORCH. Chest 136(6):1456–1465PubMedGoogle Scholar
  46. 46.
    Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C et al (2009) Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J 34(3):641–647PubMedGoogle Scholar
  47. 47.
    Kardos P, Wencker M, Glaab T, Vogelmeier C (2007) Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 175(2):144–149PubMedGoogle Scholar
  48. 48.
    Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA (2008) The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 177(1):19–26PubMedGoogle Scholar
  49. 49.
    Ernst P, Gonzalez AV, Brassard P, Suissa S (2007) Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med 176(2):162–166PubMedGoogle Scholar
  50. 50.
    Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E (2008) Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 300(20):2407–2416PubMedGoogle Scholar
  51. 51.
    Singh S, Amin AV, Loke YK (2009) Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med 169(3):219–229PubMedGoogle Scholar
  52. 52.
    Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ (1997) Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 155:542–548PubMedGoogle Scholar
  53. 53.
    Culpitt SV, Nightingale JA, Barnes PJ (1999) Effect of high dose inhaled steroid on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160:1635–1639PubMedGoogle Scholar
  54. 54.
    Loppow D, Schleiss MB, Kanniess F, Taube C, Jorres RA, Magnussen H (2001) In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation. Respir Med 95(2):115–121PubMedGoogle Scholar
  55. 55.
    Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM et al (2005) Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 352:1967–1976PubMedGoogle Scholar
  56. 56.
    Barnes PJ (2009) Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol 71:451–464PubMedGoogle Scholar
  57. 57.
    Barnes PJ (2010) Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol 120(2–3):76–85PubMedGoogle Scholar
  58. 58.
    Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ et al (2006) Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kB suppression. J Exp Med 203:7–13PubMedGoogle Scholar
  59. 59.
    To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T et al (2010) Targeting phosphoinositide-3-kinase-d with theophylline reverses corticosteroid insensitivity in COPD. Am J Respir Crit Care Med 182:897–904PubMedGoogle Scholar
  60. 60.
    Osoata G, Adcock IM, Barnes PJ, Ito K (2005) Oxidative stress causes HDAC2 reduction by nitration, ubiquitnylation and proteasomall degradation. Proc Am Thorac Soc 2:A755Google Scholar
  61. 61.
    Charron CE, Chou PC, Coutts DJ, Kumar V, To M, Akashi K et al (2009) Hypoxia inducible factor 1 alpha (HIF-1a) induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 (HDAC2) transcription. J Biol Chem 284:36047–36054PubMedGoogle Scholar
  62. 62.
    Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T et al (2002) Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 166(8):1084–1091PubMedGoogle Scholar
  63. 63.
    Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A et al (2003) Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomoised controlled trial. Lancet 361:449–456PubMedGoogle Scholar
  64. 64.
    Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S et al (2003) Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 21(1):74–81PubMedGoogle Scholar
  65. 65.
    Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H (2003) Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 22(6):912–919PubMedGoogle Scholar
  66. 66.
    Rodrigo GJ, Castro-Rodriguez JA, Plaza V (2009) Safety and efficacy of combined long-acting beta-agonists and inhaled corticosteroids vs long-acting beta-agonists monotherapy for stable COPD: a systematic review. Chest 136(4):1029–1038PubMedGoogle Scholar
  67. 67.
    Nannini L, Cates C, Lasserson T, Poole P (2007) Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 4:CD006829PubMedGoogle Scholar
  68. 68.
    La Vecchia C, Fabbri LM (2007) Prevention of death in COPD. N Engl J Med 356(21):2211–2212PubMedGoogle Scholar
  69. 69.
    ZuWallack RL, Mahler DA, Reilly D, Church N, Emmett A, Rickard K et al (2001) Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 119(6):1661–1670PubMedGoogle Scholar
  70. 70.
    Chrystyn H, Mulley BA, Peake MD (1988) Dose response relation to oral theophylline in severe chronic obstructive airway disease. Br Med J 297:1506–1510Google Scholar
  71. 71.
    Murciano D, Avclair M-H, Parievte R, Aubier M (1989) A randomized controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 320:1521–1525PubMedGoogle Scholar
  72. 72.
    Kirsten DK, Wegner RE, Jorres RA, Magnussen H (1993) Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 104(4):1101–1107PubMedGoogle Scholar
  73. 73.
    Barnes PJ (2006) Theophylline for COPD. Thorax 61(9):742–743PubMedGoogle Scholar
  74. 74.
    Zhou Y, Wang X, Zeng X, Qiu R, Xie J, Liu S et al (2006) Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology 11(5):603–610PubMedGoogle Scholar
  75. 75.
    Cosio BG, Iglesias A, Rios A, Noguera A, Sala E, Ito K et al (2009) Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of chronic obstructive pulmonary disease. Thorax 64:424–429PubMedGoogle Scholar
  76. 76.
    Culpitt SV, de Matos C, Russell RE, Donnelly LE, Rogers DF, Barnes PJ (2002) Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in COPD. Am J Respir Crit Care Med 165:1371–1376PubMedGoogle Scholar
  77. 77.
    Ford PA, Durham AL, Russell REK, Gordon F, Adcock IM, Barnes PJ (2010) Treatment effects of low dose theophylline combined with an inhaled corticosteroid in COPD. Chest 137:1338–1344PubMedGoogle Scholar
  78. 78.
    Kanehara M, Yokoyama A, Tomoda Y, Shiota N, Iwamoto H, Ishikawa N et al (2008) Anti-inflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease. Pulm Pharmacol Ther 21(6):874–878PubMedGoogle Scholar
  79. 79.
    Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ (2004) Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 200:689–695PubMedGoogle Scholar
  80. 80.
    Marwick JA, Wallis G, Meja K, Kuster B, Bouwmeester T, Chakravarty P et al (2008) Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun 377:797–802PubMedGoogle Scholar
  81. 81.
    Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA (2008) Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 178(11):1139–1147PubMedGoogle Scholar
  82. 82.
    Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ et al (2011) Azithromycin for prevention of exacerbations of COPD. N Engl J Med 365(8):689–698PubMedGoogle Scholar
  83. 83.
    Friedlander AL, Albert RK (2010) Chronic macrolide therapy in inflammatory airways diseases. Chest 138(5):1202–1212PubMedGoogle Scholar
  84. 84.
    Murphy DM, Forrest IA, Curran D, Ward C (2010) Macrolide antibiotics and the airway: antibiotic or non-antibiotic effects? Expert Opin Investig Drugs 19(3):401–414PubMedGoogle Scholar
  85. 85.
    Sugawara A, Sueki A, Hirose T, Nagai K, Gouda H, Hirono S et al (2011) Novel 12-membered non-antibiotic macrolides from erythromycin A; EM900 series as novel leads for anti-inflammatory and/or immunomodulatory agents. Bioorg Med Chem Lett 21(11):3373–3376PubMedGoogle Scholar
  86. 86.
    Kirkham P, Rahman I (2006) Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther 111(2):476–494PubMedGoogle Scholar
  87. 87.
    Grandjean EM, Berthet P, Ruffmann R, Leuenberger P (2000) Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials. Clin Ther 22(2):209–221PubMedGoogle Scholar
  88. 88.
    Poole PJ, Black PN (2001) Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. Br Med J 322:1271–1274Google Scholar
  89. 89.
    Decramer M, Rutten-van Molken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R et al (2005) Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 365(9470):1552–1560PubMedGoogle Scholar
  90. 90.
    Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L et al (2008) Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE study): a randomised placebo-controlled study. Lancet 371(9629):2013–2018PubMedGoogle Scholar
  91. 91.
    Diamant Z, Spina D (2011) PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease. Pulm Pharmacol Ther 24(4):353–360PubMedGoogle Scholar
  92. 92.
    Hatzelmann A, Morcillo EJ, Lungarella G, Adnot S, Sanjar S, Beume R et al (2010) The preclinical pharmacology of roflumilast–a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther 23(4):235–256PubMedGoogle Scholar
  93. 93.
    Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D et al (2007) Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 62(12):1081–1087PubMedGoogle Scholar
  94. 94.
    Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ (2009) Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 374(9691):685–694PubMedGoogle Scholar
  95. 95.
    Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ et al (2009) Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 374(9691):695–703PubMedGoogle Scholar
  96. 96.
    Barnes PJ (2010) New therapies for chronic obstructive pulmonary disease. Med Princ Pract 19:330–338PubMedGoogle Scholar
  97. 97.
    Barnes PJ (2004) Mediators of chronic obstructive pulmonary disease. Pharmacol Rev 56:515–548PubMedGoogle Scholar
  98. 98.
    Donnelly LE, Barnes PJ (2006) Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease. Trends Pharmacol Sci 27:546–553PubMedGoogle Scholar
  99. 99.
    Donnelly LE, Barnes PJ (2011) Chemokine receptor CXCR2 antagonism to prevent airway inflammation. Drugs Future 36(6):465Google Scholar
  100. 100.
    Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P et al (2010) SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur Respir J 35(3):564–570PubMedGoogle Scholar
  101. 101.
    Groutas WC, Dou D, Alliston KR (2011) Neutrophil elastase inhibitors. Expert Opin Ther Pat 121(11):4289–4302Google Scholar
  102. 102.
    Churg A, Wang R, Wang X, Onnervik PO, Thim K, Wright JL (2007) Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs. Thorax 62(8):706–713PubMedGoogle Scholar
  103. 103.
    Li W, Li J, Wu Y, Wu J, Hotchandani R, Cunningham K et al (2009) A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b, d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408). J Med Chem 52(7):1799–1802PubMedGoogle Scholar
  104. 104.
    Tralau-Stewart CJ, Williamson RA, Nials AT, Gascoigne M, Dawson J, Hart GJ et al (2011) GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization. J Pharmacol Exp Ther 337(1):145–154PubMedGoogle Scholar
  105. 105.
    Smith SJ, Cieslinski LB, Newton R, Donnelly LE, Fenwick PS, Nicholson AG et al (2004) Discovery of BRL 50481, a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages and CD8+ T-lymphocytes. Mol Pharmacol 66:1679–1689PubMedGoogle Scholar
  106. 106.
    Giembycz MA, Newton R (2011) Harnessing the clinical efficacy of phosphodiesterase 4 inhibitors in inflammatory lung diseases: dual-selective phosphodiesterase inhibitors and novel combination therapies. Handb Exp Pharmacol 204:415–446PubMedGoogle Scholar
  107. 107.
    Banner KH, Press NJ (2009) Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease. Br J Pharmacol 157(6):892–906PubMedGoogle Scholar
  108. 108.
    Birrell MA, Wong S, Hardaker EL, Catley MC, McCluskie K, Collins M et al (2006) IkappaB kinase-2-independent and -dependent inflammation in airway disease models: relevance of IKK-2 inhibition to the clinic. Mol Pharmacol 69(6):1791–1800PubMedGoogle Scholar
  109. 109.
    Renda T, Baraldo S, Pelaia G, Bazzan E, Turato G, Papi A et al (2008) Increased activation of p38 MAPK in COPD. Eur Respir J 31(1):62–69PubMedGoogle Scholar
  110. 110.
    Smith SJ, Fenwick PS, Nicholson AG, Kirschenbaum F, Finney-Hayward TK, Higgins LS et al (2006) Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol 149:393–404PubMedGoogle Scholar
  111. 111.
    Medicherla S, Fitzgerald M, Spicer D, Woodman P, Ma JY, Kapoun AM et al (2007) p38a selective MAP kinase inhibitor, SD-282, reduces inflammation in a sub-chronic model of tobacco smoke-induced airway inflammation. J Pharmacol Exp Ther 324:921–929PubMedGoogle Scholar
  112. 112.
    Goldstein DM, Kuglstatter A, Lou Y, Soth MJ (2010) Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem 53(6):2345–2353PubMedGoogle Scholar
  113. 113.
    Millan DS (2011) What is the potential for inhaled p38 inhibitors in the treatment of chronic obstructive pulmonary disease? Future Med Chem 3(13):1635–1645PubMedGoogle Scholar
  114. 114.
    Tudhope SJ, Finney-Hayward TK, Nicholson AG, Mayer RJ, Barnette MS, Barnes PJ et al (2008) Different mitogen-activated protein kinase-dependent cytokine responses in cells of the monocyte lineage. J Pharmacol Exp Ther 324(1):306–312PubMedGoogle Scholar
  115. 115.
    Medina-Tato DA, Ward SG, Watson ML (2007) Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond. Immunology 121(4):448–461PubMedGoogle Scholar
  116. 116.
    Ameriks MK, Venable JD (2009) Small molecule inhibitors of phosphoinositide 3-kinase (PI3K) delta and gamma. Curr Top Med Chem 9(8):738–753PubMedGoogle Scholar
  117. 117.
    Marwick JA, Caramori G, Stevenson CC, Casolari P, Jazrawi E, Barnes PJ et al (2009) Inhibition of PI3Kd restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med 179:542–548PubMedGoogle Scholar
  118. 118.
    Di Stefano A, Caramori G, Capelli A, Gnemmi I, Ricciardolo F, Oates T et al (2004) STAT4 activation in smokers and patients with chronic obstructive pulmonary disease. Eur Respir J 24:78–85PubMedGoogle Scholar
  119. 119.
    Qu P, Roberts J, Li Y, Albrecht M, Cummings OW, Eble JN et al (2009) Stat3 downstream genes serve as biomarkers in human lung carcinomas and chronic obstructive pulmonary disease. Lung Cancer 63(3):341–347PubMedGoogle Scholar
  120. 120.
    Coombs JH, Bloom BJ, Breedveld FC, Fletcher MP, Gruben D, Kremer JM et al (2010) Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 69(2):413–416PubMedGoogle Scholar
  121. 121.
    Belvisi MG, Hele DJ, Birrell MA (2006) Peroxisome proliferator-activated receptor gamma agonists as therapy for chronic airway inflammation. Eur J Pharmacol 533(1–3):101–109PubMedGoogle Scholar
  122. 122.
    Milam JE, Keshamouni VG, Phan SH, Hu B, Gangireddy SR, Hogaboam CM et al (2008) PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 294(5): L891–L901PubMedGoogle Scholar
  123. 123.
    Remels AH, Schrauwen P, Broekhuizen R, Willems J, Kersten S, Gosker HR et al (2007) Peroxisome proliferator-activated receptor expression is reduced in skeletal muscle in COPD. Eur Respir J 30(2):245–252PubMedGoogle Scholar
  124. 124.
    Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet 342:1905–1917Google Scholar
  125. 125.
    Mercado N, To Y, Ito K, Barnes PJ (2011) Nortriptyline reverses corticosteroid insensitivity by inhibition of PI3K-d. J Pharmacol Exp Ther 337:465–470PubMedGoogle Scholar
  126. 126.
    Charron C, Sumakuza T, Oomura S, Ito K (2007) EM-703, a non-antibacterial erythromycin derivative, restores HDAC2 activation diminished by hypoxia and oxidative stress. Proc Am Thorac Soc 175:A640Google Scholar
  127. 127.
    Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El Haddad H, Bedja D et al (2009) Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci U S A 106(1):250–255PubMedGoogle Scholar
  128. 128.
    Malhotra D, Thimmulappa RK, Mercado N, Ito K, Kombairaju P, Kumar S et al (2011) Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. J Clin Invest 121(11):4289–4302PubMedGoogle Scholar
  129. 129.
    Barnes PJ, Chowdhury B, Kharitonov SA, Magnussen H, Page CP, Postma D et al (2006) Pulmonary biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 174(1):6–14PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Section of Airway DiseaseNational Heart and Lung Institute, Imperial CollegeLondonUK

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