Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

New treatments for copd

Key Points

  • Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death and morbidity in the world, and is rising in prevalence throughout the world.

  • Current drug therapy concentrates on bronchodilators to reduce symptoms, and the new long-acting anticholinergic tiotropium bromide seems to be the most effective bronchodilator to date.

  • No treatment is available at present that stops the relentless progression of the disease.

  • A better understanding of the cellular and molecular mechanisms that underlie the inflammatory and destructive disease process is now pointing to several new therapeutic targets.

  • Antagonists that block inflammatory mediators that are involved in the recruitment of neutrophils, monocytes and cytotoxic T-lymphocytes are in development, including leukotriene B4 and CXC-chemokine antagonists and inhibitors of tumour-necrosis factor-α.

  • Oxidative stress is an important component of COPD, and new antioxidants and peroxynitrite inhibitors are in development.

  • Corticosteroids have little or no anti-inflammatory effect in COPD patients, so that new broad-spectrum anti-inflammatory drugs are needed. Drugs in development include phosphodiesterase-4 inhibitors, p38 mitogen-activated-protein-kinase inhibitors, and NF-κB inhibitors.

  • Proteases are responsible for the destruction of lung parenchyma that is seen in emphysema, and several elastase inhibitors are now in development.

  • The possibility of reversing emphysema with retinoic-acid-receptor agonists is also being explored.

  • New delivery systems are needed to optimize the new therapies that need to be delivered to small airways and lung parenchyma.

  • New ways to monitor the inflammation in COPD are needed to assess these new therapies in clinical studies.

Abstract

COPD is one of the most common diseases in the world, and there is a global increase in prevalence, but there are no drugs available at present that halt the relentless progression of this disease. However, a better understanding of the cellular and molecular mechanisms that are involved in the underlying inflammatory and destructive processes has revealed several new targets for which drugs are now in development, and the prospects for finding new treatments are good.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Airway pathology in COPD.
Figure 2: Annual decline in airway function.
Figure 3: Management of chronic obstructive pulmonary disease.
Figure 4: Chemokine receptors on neutrophils.
Figure 5: Targets for COPD therapy that are based on current understanding of the inflammatory mechanisms.
Figure 6: Interleukin-10 as a potential treatment for COPD.
Figure 7: Matrix metalloproteinases (MMPs) as targets in COPD therapy.

Similar content being viewed by others

References

  1. Barnes, P. J. Chronic obstructive pulmonary disease. N. Engl. J. Med. 343, 269–280 (2000).A general overview of the current understanding of the mechanisms and therapy of COPD.

    Article  CAS  PubMed  Google Scholar 

  2. Barnes, P. J. Mechanisms in COPD: differences from asthma. Chest 117, 10S–14S (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Saetta, M., Turato, G., Maestrelli, P., Mapp, C. E. & Fabbri, L. M. Cellular and structural bases of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 163, 1304–1309 (2001).A good review of the pathophysiology of COPD.

    Article  CAS  PubMed  Google Scholar 

  4. Barnes, P. J. New treatments for chronic obstructive pulmonary disease. Curr. Opin. Pharmacol. 1, 217–222 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Pauwels, R. A., Buist, S., Calverley, P. M., Jenkins, C. R. & Hurd, S. S. 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. 163, 1256–1276 (2001).The international guidelines for the diagnosis and management of COPD.

    Article  CAS  PubMed  Google Scholar 

  6. Lopez, A. D. & Murray, C. C. The global burden of disease, 1990–2020. Nature Med. 4, 1241–1243 (1998).Important predictions from the World Bank about the expected rise in mortality and morbidity from COPD compared with most other common diseases.

    Article  CAS  PubMed  Google Scholar 

  7. Appleton, S., Smith, B., Veale, A. & Bara, A. Long-acting β2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2, CD001104 (2000).

    Google Scholar 

  8. Van Noord, J. A. et al. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur. Respir. J. 15, 878–885 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Combivent Inhalation Study Group. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. Chest 112, 1514–1521 (1997).

  10. Barnes, P. J. Inhaled corticosteroids are not helpful in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 161, 342–344 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Calverley, P. M. Inhaled corticosteroids are beneficial in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 161, 341–342 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Papi, A. et al. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 162, 1773–1777 (2000).This study shows that patients with COPD who respond clinically to inhaled corticosteroid therapy have sputum eosinophils and a higher exhaled NO concentration, which indicates that they might have concomitant asthma.

    Article  CAS  PubMed  Google Scholar 

  13. Wedzicha, J. A. Domiciliary oxygen therapy services: clinical guidelines and advice for prescribers. Summary of a report of the Royal College of Physicians. J. R. Coll. Physicians. Lond. 33, 445–447 (1999).

    CAS  PubMed  Google Scholar 

  14. Lacasse, Y. et al. Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. Lancet 348, 1115–1119 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Davies, L., Angus, R. M. & Calverley, P. M. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet 354, 456–460 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Barnes, P. J. Novel approaches and targets for treatment of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 160, S72–S79 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Shapiro, S. D. Animal models for COPD. Chest 117, 223S–227S (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Hansel, T. T. & Barnes, P. J. New Drugs for Asthma and COPD (Karger, Basel, 2001).This book reviews all of the new approaches to COPD therapy that are discussed in this review in more detail.

    Book  Google Scholar 

  19. Lancaster, T., Stead, L., Silagy, C. & Sowden, A. Effectiveness of interventions to help people stop smoking: findings from the Cochrane Library. Br. Med. J. 321, 355–358 (2000).

    Article  CAS  Google Scholar 

  20. Jorenby, D. E. et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N. Engl. J. Med. 340, 685–691 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Tashkin, D. P. et al. Smoking cessation in patients with chronic obstructive pulmonary disease: a double-blind, placebo controlled, randomised trial. Lancet 357, 1571–1575 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Hughes, J. R., Stead, L. F. & Lancaster, T. Antidepressants for smoking cessation (Cochrane Review). Cochrane Database Syst. Rev. 4, CD000031 (2000).

    Google Scholar 

  23. Holm, K. J. & Spencer, C. M. Bupropion: a review of its use in the management of smoking cessation. Drugs 59, 1007–1024 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Disse, B., Speck, G. A., Rominger, K. L., Witek, T. J. & Hammer, R. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci. 64, 457–464 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Barnes, P. J. The pharmacological properties of tiotropium. Chest 117, 63S–66S (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Littner, M. R. et al. Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 161, 1136–1142 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Casaburi, R. et al. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. Chest 118, 1294–1302 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Van Noord, J. A., Bantje, T. A., Eland, M. E., Korducki, L. & Cornelissen, P. J. A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax 55, 289–294 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Casaburi, R. et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur. Respir. J. 19, 217–224 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Vincken, W. et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur. Respir. J. 19, 209–216 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Rutgers, S. R. et al. Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax 55, 12–18 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hill, A. T., Bayley, D. & Stockley, R. A. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. 160, 893–898 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Yokomizo, T., Kato, K., Terawaki, K., Izumi, T. & Shimizu, T. A second leukotriene B4 receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J. Exp. Med. 192, 421–432 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Silbaugh, S. A. et al. Pharmacologic actions of the second generation leukotriene B4 receptor antagonist LY29311: in vivo pulmonary studies. Naunyn Schmiedebergs Arch. Pharmacol. 361, 397–404 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Crooks, S. W., Bayley, D. L., Hill, S. L. & Stockley, R. A. Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4 . Eur. Respir. J. 15, 274–280 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Keatings, V. M., Collins, P. D., Scott, D. M. & Barnes, P. J. Differences in interleukin-8 and tumor necrosis factor-α in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care Med. 153, 530–534 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Yang, X. D., Corvalan, J. R., Wang, P., Roy, C. M. & Davis, C. G. Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states. J. Leukocyte Biol. 66, 401–410 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Rossi, D. & Zlotnik, A. The biology of chemokines and their receptors. Annu. Rev. Immunol. 18, 217–242 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Traves, S. L., Culpitt, S., Russell, R. E. K., Barnes, P. J. & Donnelly, L. E. Elevated levels of the chemokines GRO-α and MCP-1 in sputum samples from COPD patients. Thorax (in the press).

  40. White, J. R. et al. Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration. J. Biol. Chem. 273, 10095–10098 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Hay, D. W. P. & Sarau, H. M. Interleukin-8 receptor antagonists in pulmonary diseases. Curr. Opin. Pharmacol. 1, 242–247 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. De Boer, W. I. et al. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J. Pathol. 190, 619–626 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. Markham, A. & Lamb, H. M. Infliximab: a review of its use in the management of rheumatoid arthritis. Drugs 59, 1341–1359 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Jarvis, B. & Faulds, D. Etanercept: a review of its use in rheumatoid arthritis. Drugs 57, 945–966 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Barlaam, B. et al. New α-substituted succinate-based hydroxamic acids as TNF-α convertase inhibitors. J. Med. Chem. 42, 4890–4908 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Rabinowitz, M. H. et al. Design of selective and soluble inhibitors of tumor necrosis factor-α converting enzyme (TACE). J. Med. Chem. 44, 4252–4267 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Montuschi, P. et al. 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. 162, 1175–1177 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Paredi, P. et al. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 162, 369–373 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Macnee, W. Oxidants/antioxidants and COPD. Chest 117, 303S–317S (2000).A review of the role of oxidative stress in COPD in amplifying inflammation, and the potential role of antioxidants as therapy.

    Article  CAS  PubMed  Google Scholar 

  51. Grandjean, E. M., Berthet, P., Ruffmann, R. & Leuenberger, P. 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, 209–221 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Poole, P. J. & Black, P. N. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. Br. Med. J. 322, 1271–1274 (2001).

    Article  CAS  Google Scholar 

  53. Cuzzocrea, S., Riley, D. P., Caputi, A. P. & Salvemini, D. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol. Rev. 53, 135–159 (2001).

    CAS  PubMed  Google Scholar 

  54. Ichinose, M., Sugiura, H., Yamagata, S., Koarai, A. & Shirato, K. Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am. J. Respir. Crit. Care Med. 160, 701–706 (2000).

    Article  Google Scholar 

  55. Hobbs, A. J., Higgs, A. & Moncada, S. Inhibition of nitric oxide synthase as a potential therapeutic target. Annu. Rev. Pharmacol. Toxicol. 39, 191–220 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Vestbo, J. et al. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 353, 1819–1823 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Pauwels, R. A. et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N. Engl. J. Med. 340, 1948–1953 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Burge, P. S. et al. Randomised, double-blind, placebo-controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease; the ISOLDE trial. BMJ 320, 1297–1303 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 343, 1902–1909 (2000). | PubMed |

  60. Keatings, V. M., Jatakanon, A., Worsdell, Y. M. & Barnes, P. J. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am. J. Respir. Crit. Care Med. 155, 542–548 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Culpitt, S. V., Nightingale, J. A. & Barnes, P. J. 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, 1635–1639 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Nightingale, J. A., Rogers, D. F., Chung, K. F. & Barnes, P. J. No effect of inhaled budesonide on the response to inhaled ozone in normal subjects. Am. J. Respir. Crit. Care Med. 161, 479–486 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Meagher, L. C., Cousin, J. M., Seckl, J. R. & Haslett, C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J. Immunol. 156, 4422–4428 (1996).

    CAS  PubMed  Google Scholar 

  64. Ito, K. et al. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. 15, 1100–1102 (2001).A study that shows a reduction in histone-deacetylase activity in alveolar macrophages from cigarette smokers, which could explain the poor anti-inflammatory effects of corticosteroids in COPD.

    Article  Google Scholar 

  65. Souness, J. E., Aldous, D. & Sargent, C. Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors. Immunopharmacology 47, 127–162 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Spond, J. et al. Comparison of PDE4 inhibitors, rolipram and SB 207499 (Ariflo), in a rat model of pulmonary neutrophilia. Pulm. Pharmacol. Ther. 14, 157–164 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Bundschuh, D. S. et al. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J. Pharmacol. Exp. Ther. 297, 280–290 (2001).

    CAS  PubMed  Google Scholar 

  68. Compton, C. H. et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet 358, 265–270 (2001).The first published study to show the clinical benefit of a new anti-inflammatory drug in patients with severe COPD. Cilomilast improved lung function and symptoms significantly over a six-week period, and this was unlikely to be explained by a bronchodilator response, as the response to a β 2 -adrenoceptor agonist was unchanged at the end of the study.

    Article  CAS  PubMed  Google Scholar 

  69. Delhase, M., Li, N. & Karin, M. Kinase regulation in inflammatory response. Nature 406, 367–368 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Nasuhara, Y., Adcock, I. M., Catley, M., Barnes, P. J. & Newton, R. Differential IKK activation and IκBα degradation by interleukin-1β and tumor necrosis factor-α in human U937 monocytic cells: evidence for additional regulatory steps in κB-dependent transcription. J. Biol. Chem. 274, 19965–19972 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Davenpeck, K. L., Berens, K. L., Dixon, R. A., Dupre, B. & Bochner, B. S. Inhibition of adhesion of human neutrophils and eosinophils to P-selectin by the sialyl Lewis antagonist TBC1269: preferential activity against neutrophil adhesion in vitro. J. Allergy Clin. Immunol. 105, 769–775 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Noguera, A. et al. Enhanced neutrophil response in chronic obstructive pulmonary disease. Thorax 56, 432–437 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Takanashi, S. et al. Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers. Eur. Respir. J. 14, 309–314 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Fedorak, R. N. et al. Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. Gastroenterology 119, 1473–1482 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Carter, A. B., Monick, M. M. & Hunninghake, G. W. Both erk and p38 kinases are necessary for cytokine gene transcription. Am. J. Respir. Cell Mol. Biol. 20, 751–758 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Meja, K. K. et al. p38 MAP kinase and MKK-1 cooperate in the generation of GM-CSF from LPS-stimulated human monocytes by an NF-κB-independent mechanism. Br. J. Pharmacol. 131, 1143–1153 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lee, J. C. et al. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology 47, 185–201 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Underwood, D. C. et al. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am. J. Physiol. Lung Cell Mol. Physiol. 279, L895–L902 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Sasaki, T. et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040–1046 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Stockley, R. A. Neutrophils and protease/antiprotease imbalance. Am. J. Respir. Crit. Care Med. 160, S49–S52 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Shapiro, S. D. & Senior, R. M. Matrix metalloproteinases. Matrix degradation and more. Am. J. Respir. Cell Mol. Biol. 20, 1100–1102 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Kawabata, K. et al. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem. Biophys. Res. Commun. 177, 814–820 (1991).

    Article  CAS  PubMed  Google Scholar 

  83. Fujie, K. et al. Inhibition of elastase-induced acute inflammation and pulmonary emphysema in hamsters by a novel neutrophil elastase inhibitor FR901277. Inflamm. Res. 48, 160–167 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. Punturieri, A. et al. Regulation of elastinolytic cysteine proteinase activity in normal and cathepsin K-deficient human macrophages. J. Exp. Med. 192, 789–800 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Leung-Toung, R., Li, W., Tam, T. F. & Karimian, K. Thiol-dependent enzymes and their inhibitors: a review. Curr. Med. Chem. 9, 979–1002 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Russell, R. E. et al. Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 26, 602–609 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Massaro, G. & Massaro, D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nature Med. 3, 675–677 (1997).An important study, which shows that retinoic acid (vitamin A) can reverse the structural changes of experimental emphysema that are induced by instilled neutrophil elastase in adult rats.

    Article  CAS  PubMed  Google Scholar 

  88. Belloni, P. N., Garvin, L., Mao, C. P., Bailey-Healy, I. & Leaffer, D. Effects of all-trans-retinoic acid in promoting alveolar repair. Chest 117, 235S–241S (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Mao, J. T. et al. A pilot study of all-trans-retinoic acid for the treatment of human emphysema. Am. J. Respir. Crit. Care Med. 165, 718–723 (2002).

    Article  PubMed  Google Scholar 

  90. Barnes, P. J. Molecular genetics of chronic obstructive pulmonary disease. Thorax 54, 245–252 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kharitonov, S. A. & Barnes, P. J. Exhaled markers of pulmonary disease. Am. J. Respir. Crit. Care Med. 163, 1693–1772 (2001).A review of the new non-invasive approaches to monitoring inflammation and oxidative stress in the exhaled breath of patients with COPD.

    Article  CAS  PubMed  Google Scholar 

  92. Fletcher, C. & Peto, R. The natural history of chronic airflow obstruction. Br. Med. J. 1, 1645–1648 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASES

LocusLink

α1-antitrypsin

β2-adrenoceptor

BLT1 receptor

BLT2 receptor

cathepsin G

cathepsin K

cathepsin L

cathepsin S

CCR2

CTAP3

CXCR1

CXCR2

GCP2

histone deacetylase

ICAM-1

IκB

IKKs

IL-8

IL-10

iNOS

5-lipoxygenase

MAC-1

MCP-1

MMP-9

M1 muscarinic receptor

M3 muscarinic receptor

NAP2

neutrophil elastase

NF-κB

PDE4

PF4

PI3Ks

PI3Kγ

proteinase 3

p38 MAPK

E-selectin

SLPI

superoxide dismutase

TACE

β-TG

TIMPs

TNF-α

Medscape DrugInfo

amoxycillin

bupropion

etanercept

formoterol

infliximab

ipratropium bromide

nortryptilene

salmeterol

terbutaline

theophylline

OMIM

psoriasis

rheumatoid arthritis

FURTHER INFORMATION

Global Initiative on Obstructive Lung Disease

World Bank

World Health Organization

Glossary

EMPHYSEMA

The destruction of the lung parenchyma by proteolytic enzymes (proteases).

LUNG PARENCHYMA

The part of the lungs beyond the airways (alveoli) at which gas exchange takes place.

NEUTROPHIL

A white cell (granulocyte) that is recruited into the lungs from the circulation in COPD. Through the release of proteolytic enzymes, these cells might contribute to emphysema.

MACROPHAGE

An inflammatory cell in the lung that is derived from monocytes in the circulation. They are the scavengers of the lungs, and can produce many inflammatory mediators.

CYTOTOXIC (CD8+) T-LYMPHOCYTE

An immune cell that is recruited from the circulation that has the ability to kill infectious organisms and, also, epithelial cells in the lung.

DYSPNOEA

Shortness of breath and discomfort of breathing.

EXACERBATIONS

Worsening of COPD with increased breathlessness and sputum, which is usually caused by bacterial or viral infections.

MONOCYTE

A white blood cell in the circulation that is recruited to the lungs to differentiate into a macrophage.

CHEMOTAXIS

The movement of cells in response to a chemical gradient that is provided by chemotactic agents, such as interleukin-8 and leukotriene B4, which attract neutrophils.

BRONCHOALVEOLAR LAVAGE

The procedure that is used to obtain inflammatory cells from the lungs, which involves injecting saline down a bronchoscope and recovering the fluid, which contains inflammatory mediators and cells, such as alveolar macrophages and neutrophils, the function of which can then be studied.

ELASTOLYTIC ACTIVITY

The breakdown of elastin fibres by enzymes (elastases).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barnes, P. New treatments for copd. Nat Rev Drug Discov 1, 437–446 (2002). https://doi.org/10.1038/nrd820

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd820

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing