Download PDF
Semin Respir Crit Care Med 2005; 26(2): 142-153
DOI: 10.1055/s-2005-869535
Published by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Pathogenesis of COPD

John R. Spurzem1 , Stephen I. Rennard1
  • 1Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Further Information

Publication History

Publication Date:
27 April 2005 (online)

    Permissions and Reprints

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is characterized and defined by limitation of expiratory airflow. This can result from several types of anatomical lesions, including loss of lung elastic recoil and fibrosis and narrowing of small airways. Inflammation, edema, and secretions also contribute variably to airflow limitation. Smoking can cause COPD through several mechanisms. First, smoke is a powerful inducer of an inflammatory response. Inflammatory mediators, including oxidants and proteases, are believed to play a major role in causing lung damage. Smoke can also alter lung repair responses in several ways. Inhibition of repair may lead to tissue destruction that characterizes emphysema, whereas abnormal repair can lead to the peribronchiolar fibrosis that causes airflow limitation in small airways. Genetic factors likely play a major role and probably account for much of the heterogeneity susceptibility to smoke and other factors. Many factors may play a role, but to date, only α-1 protease inhibitor deficiency has been unambiguously identified. Exposures other than cigarette smoke can contribute to the development of COPD. Inflammation of the lower respiratory tract that results from asthma or other chronic disorders may also contribute to the development of fixed airway obstruction.

COPD is not only a disease of the lungs but is also a systemic inflammatory disorder. Muscular weakness, increased risk for atherosclerotic vascular disease, depression, osteoporosis, and abnormalities in fluids and electrolyte balance may all be consequences of COPD.

Advances in understanding the pathogenesis of COPD have the potential for identifying new therapeutic targets that could alter the natural history of this devastating disorder.

KEYWORDS

Bronchitis - emphysema - peribronchiolar fibrosis - cigarette smoking - protease - antioxidant - repair

REFERENCES

  • 1 Pauwels R A, Buist A 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. 2001;  163 1256-1276
    CrossrefPubMedGoogle Scholar
  • 2 Niewoehner D E, Sobonya R E. Structure-function correlations in chronic obstructive pulmonary disease. In: Baum GL, Wolinsky E Textbook of Pulmonary Diseases. Vol 2 Boston; Little, Brown 1994: 973-993
    Google Scholar
  • 3 Rennard S I, Daughton D M. Cigarette smoking and disease. In: Elias JA, Fishman JA, Grippi MA, Kaiser LR, Senior RM Pulmonary Diseases and Disorders New York; McGraw Hill 1998: 697-708
    Google Scholar
  • 4 Silverman E K. Genetics of chronic obstructive pulmonary disease.  Novartis Found Symp. 2001;  234 45-58
    PubMedGoogle Scholar
  • 5 Buist A S, Vollmer W M. Smoking and other risk factors. In: Murray JF, Nadel JA Textbook of Respiratory Medicine Philadelphia; WB Saunders 1994: 1259-1287
    Google Scholar
  • 6 Wouters E F, Creutzberg E C, Schols A M. Systemic effects in COPD.  Chest. 2002;  121 127S-130S
    CrossrefPubMedGoogle Scholar
  • 7 Thompson A B, Daughton D, Robbins R A, Ghafouri M A, Oehlerking M, Rennard S I. Intraluminal airway inflammation in chronic bronchitis: characterization and correlation with clinical parameters.  Am Rev Respir Dis. 1989;  140 1527-1537
    PubMedGoogle Scholar
  • 8 Thompson A B, Mueller M B, Heires A J et al.. Aerosolized beclamethasone in chronic bronchitis: improved pulmonary function and diminished airway inflammation.  Am Rev Resp Dis. 1992;  146 389-395
    PubMedGoogle Scholar
  • 9 Saetta M, Di Stefano A, Maestrelli P et al.. Airway eosinophilia and expression of interleukin-5 protein in asthma and in exacerbations of chronic bronchitis.  Clin Exp Allergy. 1996;  26 766-774
    CrossrefPubMedGoogle Scholar
  • 10 Hogg J C, Chu F, Utokaparch S et al.. The nature of small-airway obstruction in chronic obstructive pulmonary disease.  N Engl J Med. 2004;  350 2645-2653
    CrossrefPubMedGoogle Scholar
  • 11 Saetta M. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis.  Am Rev Respir Dis. 1993;  147 301-306
    PubMedGoogle Scholar
  • 12 O'Shaughnessy T C, Ansari T W, Barnes N C, Jeffery P K. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8 + T lymphocytes with FEV1 .  Am J Crit Care Med. 1997;  155 852-857
    PubMedGoogle Scholar
  • 13 Saetta M, Baraldo S, Corbino L et al.. CD8 + ve cells in the lungs of smokers with chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 1999;  160 711-717
    CrossrefPubMedGoogle Scholar
  • 14 Saetta M, Baraldo S, Turato G et al.. Increased proportion of CD8 + T-lymphocytes in the paratracheal lymph nodes of smokers with mild COPD.  Sarcoidosis Vasc Diffuse Lung Dis. 2003;  20 28-32
    PubMedGoogle Scholar
  • 15 Lams B E, Sousa A R, Rees P J, Lee T H. Subepithelial immunopathology of the large airways in smokers with and without chronic obstructive pulmonary disease.  Eur Respir J. 2000;  15 512-516
    CrossrefPubMedGoogle Scholar
  • 16 Grumelli S, Corry D B, Song L Z et al.. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema.  Plos Med. 2004;  1 e8
    CrossrefPubMedGoogle Scholar
  • 17 Grashoff W FH, Sont J K, Sterk P J et al.. Chronic obstructive pulmonary disease: role of bronchiolar mast cells and macrophages.  Am J Pathol. 1997;  151 1785-1790
    PubMedGoogle Scholar
  • 18 Kalenderian R, Raju L, Roth W, Schwartz L B, Gruber B, Janoff A. Elevated histamine and tryptase levels in smokers' bronchoalveolar lavage fluid: do lung mast cells contribute to smokers' emphysema?.  Chest. 1988;  94 119-123
    PubMedGoogle Scholar
  • 19 Lacoste J Y, Bousquet J, Chanez P et al.. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease.  J Allergy Clin Immunol. 1993;  92 537-548
    CrossrefPubMedGoogle Scholar
  • 20 Rutgers S R, Timens W, Kaufmann H F, van der Mark T W, Koeter G H, Postma D S. Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD.  Eur Respir J. 2000;  15 109-115
    PubMedGoogle Scholar
  • 21 Hargreave F E, Leigh R. Induced sputum, eosinophilic bronchitis, and chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 1999;  160 S53-S57
    PubMedGoogle Scholar
  • 22 Louis R E, Cataldo D, Buckley M G et al.. Evidence of mast-cell activation in a subset of patients with eosinophilic chronic obstructive pulmonary disease.  Eur Respir J. 2002;  20 325-331
    CrossrefPubMedGoogle Scholar
  • 23 Brightling C E, Monteiro W, Ward R et al.. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial.  Lancet. 2000;  356 1480-1485
    CrossrefPubMedGoogle Scholar
  • 24 Piquette C A, Rennard S I, Snider G L. Chronic bronchitis and emphysema. In: Murray JF, Nadel JA Textbook of Respiratory Medicine. Vol 2 Philadelphia; WB Saunders 2000: 1187-1245
    Google Scholar
  • 25 Niewoehner D E, Kleinerman J, Rice D B, Div M. Pathologic changes in the peripheral airways of young cigarette smokers.  N Engl J Med. 1974;  291 755-758
    CrossrefPubMedGoogle Scholar
  • 26 Skold C M, Hed J, Eklund A. Smoking cessation rapidly reduces cell recovery in bronchoalveolar lavage, while alveolar macrophage fluorescence remains high.  Chest. 1992;  101 989-995
    PubMedGoogle Scholar
  • 27 Turato G, Di Stefano A, Maestrelli P et al.. Effect of smoking cessation on airway inflammation in chronic bronchitis.  Am J Respir Crit Care Med. 1995;  152 1262-1267
    PubMedGoogle Scholar
  • 28 Rutgers S R, Postma D S, ten Hacken N H et al.. Ongoing airway inflammation in patients with COPD who do not currently smoke.  Thorax. 2000;  55 12-18
    CrossrefPubMedGoogle Scholar
  • 29 Buist A S, Sexton G J, Nagy J M, Ross B B. The effect of smoking cessation and modification on lung function.  Am Rev Respir Dis. 1976;  114 115-122
    PubMedGoogle Scholar
  • 30 Anthonisen N R, Connett J E, Kiley J P et al.. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1 .  JAMA. 1994;  272 1497-1505
    CrossrefPubMedGoogle Scholar
  • 31 Balbi B. COPD: is chemotaxis the key?.  Chest. 2003;  123 983-986
    CrossrefPubMedGoogle Scholar
  • 32 Traves S L, Culpitt S V, Russell R E, Barnes P J, Donnelly L E. Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD.  Thorax. 2002;  57 590-595
    CrossrefPubMedGoogle Scholar
  • 33 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. 1996;  153 530-534
    PubMedGoogle Scholar
  • 34 Beeh K M, Beier J, Kornmann O, Mander A, Buhl R. Long-term repeatability of induced sputum cells and inflammatory markers in stable, moderately severe COPD.  Chest. 2003;  123 778-783
    CrossrefPubMedGoogle Scholar
  • 35 de Boer W I, Sont J K, van Schadewijk A, Stolk J, van Krieken J H, Hiemstra P S. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD.  J Pathol. 2000;  190 619-626
    PubMedGoogle Scholar
  • 36 Saetta M, Mariani M, Panina-Bordignon P et al.. Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2002;  165 1404-1409
    CrossrefPubMedGoogle Scholar
  • 37 Tanino M, Betsuyaku T, Takeyabu K et al.. Increased levels of interleukin-8 in BAL fluid from smokers susceptible to pulmonary emphysema.  Thorax. 2002;  57 405-411
    CrossrefPubMedGoogle Scholar
  • 38 Pesci A, Balbi B, Majori M et al.. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease.  Eur Respir J. 1998;  12 380-386
    CrossrefPubMedGoogle Scholar
  • 39 Pryzwansky K B, Wyatt T A, Lincoln T M. Cyclic guanosine monophosphate-dependent protein kinase is targeted to intermediate filaments and phosphorylates vimentin in A23187-stimulated human neutrophils.  Blood. 1995;  85 222-230
    PubMedGoogle Scholar
  • 40 Laudanna C, Campbell J J, Butcher E C. Elevation of intracellular cAMP inhibits RhoA activation and integrin-dependent leukocyte adhesion induced by chemoattractants.  J Biol Chem. 1997;  272 24141-24144
    CrossrefPubMedGoogle Scholar
  • 41 Culpitt S V, de Matos C, Russell R E, Donnelly L E, Rogers D F, Barnes P J. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2002;  165 1371-1376
    CrossrefPubMedGoogle Scholar
  • 42 Rennard S I, Thompson A, Daughton D et al.. Theophylline reduces neutrophil recruitment in vitro and lowers airway neutrophilia in chronic bronchitis in vivo.  Eur Respir J. 1990;  3 116S
    PubMedGoogle Scholar
  • 43 Vignola A M. PDE4 inhibitors in COPD: a more selective approach to treatment.  Respir Med. 2004;  98 495-503
    PubMedGoogle Scholar
  • 44 Page K, Li J, Zhou L et al.. Regulation of airway epithelial cell NF-kappa B-dependent gene expression by protein kinase C delta.  J Immunol. 2003;  170 5681-5689
    PubMedGoogle Scholar
  • 45 Monick M, Staber J, Thomas K, Hunninghake G. Respiratory syncytial virus infection results in activation of multiple protein kinase C isoforms leading to activation of mitogen-activated protein kinase.  J Immunol. 2001;  166 2681-2687
    PubMedGoogle Scholar
  • 46 Monick M M, Hunninghake G W. Second messenger pathways in pulmonary host defense.  Annu Rev Physiol. 2003;  65 643-667
    CrossrefPubMedGoogle Scholar
  • 47 Romberger D J, Bodlak V, Von Essen S G, Mathisen T, Wyatt T A. Hog barn dust extract stimulates IL-8 and IL-6 release in human bronchial epithelial cells via PKC activation.  J Appl Physiol. 2002;  93 289-296
    PubMedGoogle Scholar
  • 48 Wyatt T A, Heires A J, Sanderson S D, Floreani A A. Protein kinase C activation is required for cigarette smoke-enhanced C5a-mediated release of interleukin-8 in human bronchial epithelial cells.  Am J Respir Cell Mol Biol. 1999;  21 283-288
    PubMedGoogle Scholar
  • 49 Floreani A A, Wyatt T A, Stoner J et al.. Smoke and C5a induce airway epithelial intercellular adhesion molecule-1 and cell adhesion.  Am J Respir Cell Mol Biol. 2003;  29 472-482
    CrossrefPubMedGoogle Scholar
  • 50 Zheng T, Zhu Z, Wang Z et al.. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema.  J Clin Invest. 2000;  106 1081-1093
    CrossrefPubMedGoogle Scholar
  • 51 Wang Z, Zheng T, Zhu Z et al.. Interferon gamma induction of pulmonary emphysema in the adult murine lung.  J Exp Med. 2000;  192 1587-1600
    CrossrefPubMedGoogle Scholar
  • 52 Laurell C B, Eriksson S. The electrophoretic alpha 1-globulin pattern of serum in alpha 1-antitrypsin deficiency.  Scand J Clin Lab Invest. 1963;  15 132-140
    CrossrefPubMedGoogle Scholar
  • 53 Gross P, Babjak M, Tolker E et al.. Enzymatically produced pulmonary emphysema: A preliminary report.  J Occup Med. 1964;  6 481-484
    PubMedGoogle Scholar
  • 54 Janoff A, Sloan B, Weinbaum G et al.. Experimental emphysema induced with purified human neutrophil elastase: tissue localization of the instilled protease.  Am Rev Resp Dis. 1977;  115 461-478
    PubMedGoogle Scholar
  • 55 Senior R M, Tegner H, Kuhn C, Ohlsson K, Starcher B C, Pierce J A. The induction of pulmonary emphysema with human leukocyte elastase.  Am Rev Resp Dis. 1977;  116 469-475
    PubMedGoogle Scholar
  • 56 Nolte S, Skov P S. Inhibition of basophil histamine release by methotrexate.  Agents Actions. 1988;  23 173-176
    PubMedGoogle Scholar
  • 57 Travis J. Structure, function and control of neutrophil proteinases.  Am J Med. 1988;  84 37-43
    PubMedGoogle Scholar
  • 58 Shapiro S D, Senior R M. Matrix metalloproteinases: matrix degradation and more.  Am J Respir Cell Mol Biol. 1999;  20 1100-1102
    PubMedGoogle Scholar
  • 59 Chapman H, Riese R, Shi G. Emerging roles for cysteine proteases in human biology.  Annu Rev Physiol. 1997;  59 63-88
    CrossrefPubMedGoogle Scholar
  • 60 Takeyabu K, Betsuyaku T, Nishimura M et al.. Cysteine proteinases and cystatin C in bronchoalveolar lavage fluid from subjects with subclinical emphysema.  Eur Respir J. 1998;  12 1033-1039
    CrossrefPubMedGoogle Scholar
  • 61 Segura-Valdez L, Pardo A, Gaxiola M, Uhal B D, Becerril C, Selman M. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD.  Chest. 2000;  117 684-694
    CrossrefPubMedGoogle Scholar
  • 62 Fujita J, Nelson N L, Daughton D M et al.. Evaluation of elastase and antielastase balance in patients with bronchitis and pulmonary emphysema.  Am Rev Respir Dis. 1990;  142 57-62
    PubMedGoogle Scholar
  • 63 Cataldo D, Munaut C, Noel A et al.. MMP-2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease.  Int Arch Allergy Immunol. 2000;  123 259-267
    CrossrefPubMedGoogle Scholar
  • 64 Montano M, Beccerril C, Ruiz V, Ramos C, Sansores R H, Gonzalez-Avila G. Matrix metalloproteinases activity in COPD associated with wood smoke.  Chest. 2004;  125 466-472
    CrossrefPubMedGoogle Scholar
  • 65 Janoff A. Reduction of the elastase in inhibitory capacity of alpha-1-antitrypsin by peroxides in cigarette smoke: an analysis of the brands and the filters.  Am Rev Respir Dis. 1982;  126 25-30
    PubMedGoogle Scholar
  • 66 Gadek J, Fells G A, Crystal R G. Cigarette smoking induces functional antiprotease deficiency in lower respiratory tract of humans.  Science. 1979;  206 1315-1316
    PubMedGoogle Scholar
  • 67 Campbell E J, Campbell M A, Boukedes S S, Owen C A. Quantum proteolysis by neutrophils: implications for pulmonary emphysema in α1-antitrypsin deficiency.  J Clin Invest. 1999;  104 337-344
    PubMedGoogle Scholar
  • 68 Taggart C C, Lowe G J, Greene C M et al.. Cathepsin B, L, and S cleave and inactivate secretory leucoprotease inhibitor.  J Biol Chem. 2001;  276 33345-33352
    CrossrefPubMedGoogle Scholar
  • 69 Okada Y, Watanabe S, Nakanishi I et al.. Inactivation of tissue inhibitor of metalloproteinases by neutrophil elastase and other serine proteinases.  FEBS Lett. 1988;  229 157-160
    CrossrefPubMedGoogle Scholar
  • 70 Hautamaki R D, Kobayashi D K, Senior R M, Shapiro S D. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice.  Science. 1997;  277 2002-2004
    CrossrefPubMedGoogle Scholar
  • 71 Dangelo M, Sarment D P, Billings P C, Pacifici M. Activation of transforming growth factor beta in chondrocytes undergoing endochondral ossification.  J Bone Miner Res. 2001;  16 2339-2347
    PubMedGoogle Scholar
  • 72 Churg A, Wang R D, Tai H et al.. Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release.  Am J Respir Crit Care Med. 2003;  167 1083-1089
    CrossrefPubMedGoogle Scholar
  • 73 Skold C M, Liu X, Umino T et al.. Human neutrophil elastase augments fibroblast-mediated contraction of released collagen gels.  Am J Respir Crit Care Med. 1999;  159 1138-1146
    PubMedGoogle Scholar
  • 74 Kohri K, Ueki I F, Nadel J A. Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation.  Am J Physiol Lung Cell Mol Physiol. 2002;  283 L531-L540
    PubMedGoogle Scholar
  • 75 MacNee W. Oxidants/antioxidants and chronic obstructive pulmonary disease: pathogenesis to therapy.  Novartis Found Symp. 2001;  234 169-185
    PubMedGoogle Scholar
  • 76 Rahman I, Li X Y, Donaldson K, Harrison D J, MacNee W. Glutathione homeostasis in alveolar epithelial cells in vitro and lung in vivo under oxidative stress.  Am J Physiol. 1995;  269 L285-L292
    PubMedGoogle Scholar
  • 77 Choi A M, Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury.  Am J Respir Cell Mol Biol. 1996;  15 9-19
    PubMedGoogle Scholar
  • 78 Otterbein L E, Kolls J K, Mantell L L, Cook J L, Alam J, Choi A M. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury.  J Clin Invest. 1999;  103 1047-1054
    PubMedGoogle Scholar
  • 79 Yamada N, Yamaya M, Okinaga S et al.. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema.  Am J Hum Genet. 2000;  66 187-195
    CrossrefPubMedGoogle Scholar
  • 80 Maestrelli P, El Messlemani A H, De Fina O et al.. Increased expression of heme oxygenase (HO)-1 in alveolar spaces and HO-2 in alveolar walls of smokers.  Am J Respir Crit Care Med. 2001;  164 1508-1513
    CrossrefPubMedGoogle Scholar
  • 81 Maestrelli P, Paska C, Saetta M et al.. Decreased haem oxygenase-1 and increased inducible nitric oxide synthase in the lung of severe COPD patients.  Eur Respir J. 2003;  21 971-976
    PubMedGoogle Scholar
  • 82 Ito K, Hanazawa T, Tomita K, Barnes P J, Adcock I M. Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration.  Biochem Biophys Res Commun. 2004;  315 240-245
    CrossrefPubMedGoogle Scholar
  • 83 Ito K, Barnes P J, Adcock I M. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12.  Mol Cell Biol. 2000;  20 6891-6903
    CrossrefPubMedGoogle Scholar
  • 84 Takeyama K, Dabbagh K, Jeong Shim J, Dao-Pick T, Ueki I F, Nadel J A. Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils.  J Immunol. 2000;  164 1546-1552
    PubMedGoogle Scholar
  • 85 Rahman I, Marwick J, Kirkham P. Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression.  Biochem Pharmacol. 2004;  68 1255-1267
    CrossrefPubMedGoogle Scholar
  • 86 Takeyama K, Jung B, Shim J J et al.. Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke.  Am J Physiol Lung Cell Mol Physiol. 2001;  280 L165-L172
    PubMedGoogle Scholar
  • 87 MacNee W. Oxidants/antioxidants and COPD.  Chest. 2000;  117(suppl 1) 303S-317S
    CrossrefPubMedGoogle Scholar
  • 88 Liebow A A. Pulmonary emphysema with special reference to vascular changes.  Am Rev Respir Dis. 1959;  80 67-93
    PubMedGoogle Scholar
  • 89 Kasahara Y, Tuder R M, Taraseviciene-Stewart L et al.. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema.  J Clin Invest. 2000;  106 1311-1319
    CrossrefPubMedGoogle Scholar
  • 90 Tang K, Rossiter H B, Wagner P D, Breen E C. Lung-targeted VEGF inactivation leads to an emphysema phenotype in mice.  J Appl Physiol. 2004;  97 1559-1566
    CrossrefPubMedGoogle Scholar
  • 91 Tsao P N, Su Y N, Li H et al.. Overexpression of placenta growth factor contributes to the pathogenesis of pulmonary emphysema.  Am J Respir Crit Care Med. 2004;  169 505-511
    PubMedGoogle Scholar
  • 92 Aoshiba K, Yokohori N, Nagai A. Alveolar wall apoptosis causes lung destruction and emphysematous changes.  Am J Respir Cell Mol Biol. 2003;  28 555-562
    CrossrefPubMedGoogle Scholar
  • 93 Kasahara Y, Tuder R M, Cool C D, Lynch D A, Flores S C, Voelkel N F. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema.  Am J Respir Crit Care Med. 2001;  163 737-744
    CrossrefPubMedGoogle Scholar
  • 94 Grossmann J. Molecular mechanisms of “detachment-induced apoptosis-Anoikis.”  Apoptosis. 2002;  7 247-260
    CrossrefPubMedGoogle Scholar
  • 95 Morse D, Choi A M. Heme oxygenase-1: the “emerging molecule” has arrived.  Am J Respir Cell Mol Biol. 2002;  27 8-16
    PubMedGoogle Scholar
  • 96 Aoshiba K, Tamaoki J, Nagai A. Acute cigarette smoke exposure induces apoptosis of alveolar macrophages.  Am J Physiol Lung Cell Mol Physiol. 2001;  281 L1392-L1401
    PubMedGoogle Scholar
  • 97 Carnevali S, Petruzzelli S, Longoni B et al.. Cigarette smoke extract induces oxidative stress and apoptosis in human lung fibroblasts.  Am J Physiol Lung Cell Mol Physiol. 2003;  284 L955-L963
    PubMedGoogle Scholar
  • 98 Wickenden J A, Clarke M C, Rossi A G et al.. Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis.  Am J Respir Cell Mol Biol. 2003;  29 562-570
    CrossrefPubMedGoogle Scholar
  • 99 Kim H, Liu X, Kobayashi T et al.. Reversible cigarette smoke extract-induced DNA damage in human lung fibroblasts.  Am J Respir Cell Mol Biol. 2004;  31 483-490
    CrossrefPubMedGoogle Scholar
  • 100 Verra F, Escudier E, Lebargy F, Bernaudin J F, De-Cremoux H, Bignon J. Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers.  Am J Respir Crit Care Med. 1995;  151 630-634
    PubMedGoogle Scholar
  • 101 Lee H M, Takeyama K, Dabbagh K, Lausier J A, Ueki I F, Nadel J A. Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways.  Am J Physiol Lung Cell Mol Physiol. 2000;  278 L185-L192
    PubMedGoogle Scholar
  • 102 Daughton D M, Matthews K, Romberger D J et al.. Smoking cessation reduces lower respiratory tract inflammation in healthy smokers.  Society for Research on Nicotine and Tobacco. February 19, 2004;  , Phoenix, AZ. Available at www.srnt.org/pubs/abstract.html
    PubMedGoogle Scholar
  • 103 Rennard S I. Repair. In: Calverley PMA, MacNee W, Pride NB, Rennard SI Chronic Obstructive Pulmonary Disease London; Arnold 2003: 139-150
    Google Scholar
  • 104 Wiggs B R, Bosken C, Pare P D, James A, Hogg J C. A model of airway narrowing in asthma and in chronic obstructive pulmonary disease.  Am Rev Respir Dis. 1992;  145 1251-1258
    PubMedGoogle Scholar
  • 105 Roberts A B. Molecular and cell biology of TGF-beta.  Miner Electrolyte Metab. 1998;  24 111-119
    CrossrefPubMedGoogle Scholar
  • 106 Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing.  J Dermatol Sci. 2004;  35 83-92
    CrossrefPubMedGoogle Scholar
  • 107 Raghow R, Postlethwaite A E, Keski-Oja J, Moses H L, Kang A H. Transforming growth factor-beta increases steady state levels of type I procollagen and fibronectin messenger RNAs posttranscriptionally in cultured human dermal fibroblasts.  J Clin Invest. 1987;  79 1285-1288
    PubMedGoogle Scholar
  • 108 Fine A, Goldstein R H. The effect of transforming growth factor-beta on cell proliferation and collagen formation by lung fibroblasts.  J Biol Chem. 1987;  262 3897-3902
    PubMedGoogle Scholar
  • 109 Lucas P A, Caplan A I. Chemotactic response of embryonic limb bud mesenchymal cells and muscle-derived fibroblasts to transforming growth factor-beta.  Connect Tissue Res. 1988;  18 1-7
    PubMedGoogle Scholar
  • 110 Mio T, Liu X, Adachi Y et al.. Human bronchial epithelial cells modulate collagen gel contraction by fibroblasts.  Am J Physiol. 1998;  274 L119-L126
    PubMedGoogle Scholar
  • 111 Liu X, Wen F Q, Kobayashi T et al.. Smad3 mediates the TGF-beta induced contraction of type 1 collagen gels by mouse embryo fibroblasts.  Cell Motil Cytoskeleton. 2003;  54 248-253
    CrossrefPubMedGoogle Scholar
  • 112 Liu X, Kohyama T, Wang H et al.. Th2 cytokine regulation of type I collagen gel contraction mediated by human lung mesenchymal cells.  Am J Physiol Lung Cell Mol Physiol. 2002;  282 L1049-L1056
    PubMedGoogle Scholar
  • 113 Saito A, Okazaki H, Sugawara I, Yamamoto K, Takizawa H. Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro.  Int Arch Allergy Immunol. 2003;  132 168-176
    CrossrefPubMedGoogle Scholar
  • 114 Miotto D, Ruggieri M P, Boschetto P et al.. Interleukin-13 and -4 expression in the central airways of smokers with chronic bronchitis.  Eur Respir J. 2003;  22 602-608
    PubMedGoogle Scholar
  • 115 Pierce J A, Hocott J B, Ebert R V. The collagen and elastin content of the lung in emphysema.  Ann Intern Med. 1961;  55 210-221
    PubMedGoogle Scholar
  • 116 Lang M R, Fiaux G W, Gillooly M, Stewart J A, Hulmes D JS, Lamb D. Collagen content of alveolar wall tissue in emphysematous and nonemphysematous lungs.  Thorax. 1994;  49 319-326
    PubMedGoogle Scholar
  • 117 Kuhn C, Yu S Y, Chraplyvy M. The induction of emphysema with elastase, II: Changes in connective tissue.  Lab Invest. 1976;  34 372-380
    PubMedGoogle Scholar
  • 118 Nakamura Y, Romberger D J, Tate L et al.. Cigarette smoke inhibits lung fibroblast proliferation and chemotaxis.  Am J Respir Crit Care Med. 1995;  151 1497-1503
    PubMedGoogle Scholar
  • 119 Carnevali S, Nakamura Y, Mio T et al.. Cigarette smoke extract inhibits fibroblast-mediated collagen gel contraction.  Am J Physiol Lung Cell Mol Physiol. 1998;  274 L591-L598
    PubMedGoogle Scholar
  • 120 Wang H, Liu X, Umino T et al.. Effect of cigarette smoke on fibroblast-mediated gel contraction is dependent on cell density.  Am J Physiol Lung Cell Mol Physiol. 2003;  284 L205-L213
    PubMedGoogle Scholar
  • 121 Kohyama T, Ertl R F, Valenti V et al.. Prostaglandin E2 inhibits fibroblast chemotaxis.  Am J Physiol Lung Cell Mol Physiol. 2001;  281 L1257-L1263
    PubMedGoogle Scholar
  • 122 Bitterman P B, Wewers M D, Rennard S I, Adelberg S, Crystal R G. Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators.  J Clin Invest. 1986;  77 700-708
    PubMedGoogle Scholar
  • 123 Mio T, Adachi Y, Carnevali S, Romberger D J, Spurzem J R, Rennard S I. Beta-adrenergic agonists attenuate fibroblast-mediated contraction of released collagen gels.  Am J Physiol. 1996;  270 L829-L835
    PubMedGoogle Scholar
  • 124 Kohyama T, Liu X, Wen F Q et al.. PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels.  Am J Respir Cell Mol Biol. 2002;  26 694-701
    PubMedGoogle Scholar
  • 125 Massaro G D, Massaro D. Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats.  Am J Physiol. 1996;  270 L305-L310
    PubMedGoogle Scholar
  • 126 Massaro D, Massaro G D. Pulmonary alveolus formation: critical period, retinoid regulation and plasticity.  Novartis Found Symp. 2001;  234 229-236 , discussion 236-241
    PubMedGoogle Scholar
  • 127 Massaro G, Massaro D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats.  Nat Med. 1997;  3 675-677
    CrossrefPubMedGoogle Scholar
  • 128 Hind M, Maden M. Retinoic acid induces alveolar regeneration in the adult mouse lung.  Eur Respir J. 2004;  23 20-27
    CrossrefPubMedGoogle Scholar
  • 129 Massaro G D, Massaro D. Retinoic acid treatment partially rescues failed septation in rats and in mice.  Am J Physiol Lung Cell Mol Physiol. 2000;  278 L955-L960
    PubMedGoogle Scholar
  • 130 Lucey E C, Goldstein R H, Breuer R, Rexer B N, Ong D E, Snider G L. Retinoic acid does not affect alveolar septation in adult FVB mice with elastase-induced emphysema.  Respiration . 2003;  70 200-205
    CrossrefPubMedGoogle Scholar
  • 131 March T H, Cossey P Y, Esparza D C, Dix K J, McDonald J D, Bowen L E. Inhalation administration of all-trans-retinoic acid for treatment of elastase-induced pulmonary emphysema in Fischer 344 rats.  Exp Lung Res. 2004;  30 383-404
    CrossrefPubMedGoogle Scholar
  • 132 Fujita M, Ye Q, Ouchi H et al.. Retinoic acid fails to reverse emphysema in adult mouse models.  Thorax. 2004;  59 224-230
    CrossrefPubMedGoogle Scholar
  • 133 Comstock G W, Menkes M S, Schober S E, Vuilleumier J P, Helsing K J. Serum levels of retinol, beta-carotene, and alpha-tocopherol in older adults.  Am J Epidemiol. 1988;  127 114-123
    PubMedGoogle Scholar
  • 134 Schunemann H J, Grant B J, Freudenheim J L et al.. The relation of serum levels of antioxidant vitamins C and E, retinol and carotenoids with pulmonary function in the general population.  Am J Respir Crit Care Med. 2001;  163 1246-1255
    PubMedGoogle Scholar
  • 135 Wouters E F. Chronic obstructive pulmonary disease, V: Systemic effects of COPD.  Thorax. 2002;  57 1067-1070
    CrossrefPubMedGoogle Scholar
  • 136 Casaburi R. Skeletal muscle function in COPD.  Chest. 2000;  117(suppl 1) 267S-271S
    CrossrefPubMedGoogle Scholar
  • 137 Ashley F, Kannel W B, Sorlie P D, Masson R. Pulmonary function: relation to aging, cigarette habit, and mortality.  Ann Intern Med. 1975;  82 739-745
    PubMedGoogle Scholar
  • 138 Sin D D, Man S F. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease.  Circulation. 2003;  107 1514-1519
    CrossrefPubMedGoogle Scholar
  • 139 Mannino D M, Buist A S, Petty T L, Enright P L, Redd S C. Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study.  Thorax. 2003;  58 388-393
    CrossrefPubMedGoogle Scholar
  • 140 Debigare R, Marquis K, Cote C H et al.. Catabolic/anabolic balance and muscle wasting in patients with COPD.  Chest. 2003;  124 83-89
    CrossrefPubMedGoogle Scholar
  • 141 Schols A M, Mostert R, Soeters P B, Wouters E F. Body composition and exercise performance in patients with chronic obstructive pulmonary disease.  Thorax. 1991;  46 695-699
    CrossrefPubMedGoogle Scholar
  • 142 Panel AAPRG . Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based guidelines. ACCP/AACVPR Pulmonary Rehabilitation Guidelines Panel. American College of Chest Physicians.  American Association of Cardiovascular and Pulmonary Rehabilitation, Chest. 1997;  112 1363-1396
    PubMedGoogle Scholar
  • 143 Gosker H R, Kubat B, Schaart G, van der Vusse G J, Wouters E F, Schols A M. Myopathological features in skeletal muscle of patients with chronic obstructive pulmonary disease.  Eur Respir J. 2003;  22 280-285
    CrossrefPubMedGoogle Scholar
  • 144 Maltais F, LeBlanc P, Whittom F et al.. Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD.  Thorax. 2000;  55 848-853
    CrossrefPubMedGoogle Scholar
  • 145 Agusti A G, Sauleda J, Miralles C et al.. Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2002;  166 485-489
    CrossrefPubMedGoogle Scholar
  • 146 Di Francia M, Barbier D, Mege J L, Orehek J. Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 1994;  150 1453-1455
    PubMedGoogle Scholar
  • 147 Yamamoto C, Yoneda T, Yoshikawa M et al.. The relationship between a decrease in fat mass and serum levels of TNF-alpha in patients with chronic obstructive pulmonary disease.  Nihon Kyobu Shikkan Gakkai Zasshi. 1997;  35 1191-1195
    PubMedGoogle Scholar
  • 148 Eid A A, Ionescu A A, Nixon L S et al.. Inflammatory response and body composition in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2001;  164 1414-1418
    CrossrefPubMedGoogle Scholar
  • 149 Schols A M, Creutzberg E C, Buurman W A, Campfield L A, Saris W H, Wouters E F. Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 1999;  160 1220-1226
    PubMedGoogle Scholar
  • 150 Takabatake N, Nakamura H, Abe S et al.. The relationship between chronic hypoxemia and activation of the tumor necrosis factor-alpha system in patients with chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2000;  161 1179-1184
    PubMedGoogle Scholar
  • 151 Nguyen L T, Bedu M, Caillaud D et al.. Increased resting energy expenditure is related to plasma TNF-alpha concentration in stable COPD patients [see comments].  Clin Nutr. 1999;  18 269-274
    PubMedGoogle Scholar
  • 152 Karadag F, Karul A B, Cildag O, Altun C, Gurgey O. Determinants of BMI in patients with COPD.  Respirology. 2004;  9 70-75
    CrossrefPubMedGoogle Scholar
  • 153 Calikoglu M, Sahin G, Unlu A et al.. Leptin and TNF-alpha levels in patients with chronic obstructive pulmonary disease and their relationship to nutritional parameters.  Respiration. 2004;  71 45-50
    CrossrefPubMedGoogle Scholar
  • 154 Schols A M, Slangen J, Vovovics L, Wouters E F. Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 1998;  157 1791-1797
    CrossrefPubMedGoogle Scholar
  • 155 Chailleux E, Bauroux B, Binet F, Dautzenberg B, Polu J-M. Predictors of survival in patients receiving domiciliary oxygen therapy or mechanical ventilation.  Chest. 1996;  109 741-749
    CrossrefPubMedGoogle Scholar
  • 156 Sullivan P F, Kendler K S. The genetic epidemiology of smoking.  Nicotine Tob Res. 1999;  1(Suppl 2) S51-S57 , discussion S69-S70
    PubMedGoogle Scholar
  • 157 Sin D D, Man J P, Man S F. The risk of osteoporosis in Caucasian men and women with obstructive airways disease.  Am J Med. 2003;  114 10-14
    CrossrefPubMedGoogle Scholar
  • 158 Ionescu A A, Schoon E. Osteoporosis in chronic obstructive pulmonary disease.  Eur Respir J Suppl. 2003;  46 64s-75s
    PubMedGoogle Scholar
  • 159 Peat J K, Woolcock A J, Cullen K. Rate of decline of lung function in subjects with asthma.  Eur J Respir Dis. 1987;  70 171-179
    PubMedGoogle Scholar
  • 160 Lange P, Parner J, Vestbo J, Schnor P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma.  N Engl J Med. 1998;  339 1194-1200
    CrossrefPubMedGoogle Scholar
  • 161 Ulrik C S, Backer V. Nonreversible airflow obstruction in life-long nonsmokers with moderate to severe asthma.  Eur Respir J. 1999;  14 892-896
    CrossrefPubMedGoogle Scholar
  • 162 Barker D JP, Godfrey K M, Fall C HD, Osmond C, Winter P D, Shaheen S O. Relation of birthweight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease.  BMJ. 1991;  303 671-675
    CrossrefPubMedGoogle Scholar
  • 163 Shaheen S O, Sterne J A, Florey C D. Birth weight, childhood lower respiratory tract infection, and adult lung function.  Thorax. 1998;  53 549-553
    PubMedGoogle Scholar
  • 164 Sherrill D L, Lebowitz M D, Knudson R J, Burrows B. Smoking and symptom effects on the curves of lung function growth and decline.  Am Rev Respir Dis. 1991;  144 17-22
    CrossrefPubMedGoogle Scholar
  • 165 Tager I, Segal M, Speizer F, Weiss S. The natural history of forced expiratory volumes.  Am Rev Respir Dis. 1988;  138 837-849
    CrossrefPubMedGoogle Scholar

John R SpurzemM.D. 

University of Nebraska Medical Center, 985300 Nebraska Medical Center

Omaha, NE 68198-5300

Email: jspurzem@unmc.edu

      >