Chronic obstructive pulmonary disease: Molecular and cellular mechanisms

European Respiratory Journal

Volumn 22, Issue 4, 2003, Pages 672-688

  Barnes, P J ^a   Shapiro, S D ^b   Pauwels, R A ^c  

^a NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c GHENT UNIVERSITY HOSPITAL   (Belgium)

Author keywords

Chemokine; Cytokine; Emphysema; Macrophage; Oxidative stress; Protease

Indexed keywords

ANTIINFLAMMATORY AGENT; CATHEPSIN; CORTICOSTEROID; CYSTEINE PROTEINASE; CYTOKINE; GROWTH FACTOR; LEUKOCYTE ELASTASE; LIPID; MATRIX METALLOPROTEINASE; SERINE PROTEINASE;

AIRWAY CONSTRICTION; ASTHMA; CAUSE OF DEATH; CELL COUNT; CHRONIC OBSTRUCTIVE LUNG DISEASE; CIGARETTE SMOKING; CYTOKINE RELEASE; CYTOTOXIC T LYMPHOCYTE; ELASTOLYSIS; EMPHYSEMA; HUMAN; LUNG ALVEOLUS MACROPHAGE; LUNG ALVEOLUS WALL; MOLECULAR MECHANICS; NEUTROPHIL; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PHYSICAL DISABILITY; PRIORITY JOURNAL; PROTEIN DEGRADATION; RESPIRATORY TRACT INFLAMMATION; REVIEW;

EID: 0141928029     PISSN: 09031936     EISSN: None     Source Type: Journal    
DOI: 10.1183/09031936.03.00040703     Document Type: Review

References (265)

1. Lopez AD, Murray CC. The global burden of disease, 1990-2020. Nat Med 1998; 4: 1241-1243.
2. Barnes PJ. Chronic obstructive pulmonary disease. New Engl J Med 2000; 343: 269-280.
3. Barnes PJ. New treatments for chronic obstructive pulmonary disease. Curr Opin Pharmacol 2001; 1: 217-222.
4. Barnes PJ. New concepts in COPD. Ann Rev Med 2003; 54: 113-129.
5. Gross CP, Anderson GF, Powe NR. The relation between funding by the National Institutes of Health and the burden of disease. N Engl J Med 1999; 340: 1881-1887.
6. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. 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.
7. Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular and structural bases of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 1304-1309.
8. Fabbri LM, Romagnoli M, Corbetta L, et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167: 418-424.
9. Saetta M, Di Stefano A, Turato G, et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 822-826.
10. Di Stefano A, Capelli A, Lusuardi M, et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998; 158: 1277-1285.
11. 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.
12. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-a in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996; 153: 530-534.
13. Fabbri L, Beghe B, Caramori G, Papi A, Saetta M. Similarities and discrepancies between exacerbations of asthma and chronic obstructive pulmonary disease. Thorax 1998; 53: 803-808.
14. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968; 278: 1355-1360.
15. Cosio M, Ghezzo H, Hogg JC, et al. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med 1978; 298: 1277-1281.
16. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 1974; 291: 755-758.
17. Gelb AF, Hogg JC, Muller NL, et al. Contribution of emphysema and small airways in COPD. Chest 1996; 109: 353-359.
18. Chu FSF, Utokaparch S, Butazu L, et al. The nature of airay obstruction in COPD. Am J Respir Crit Care Med 2003; 167: A874.
19. de Boer WI, van Schadewijk A, Sont JK, et al. Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158: 1951-1957.
20. Takizawa H, Tanaka M, Takami K, et al. Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 2001; 163: 1476-1483.
21. Ihn H. Pathogenesis of fibrosis: role of TGF-b and CTGF. Curr Opin Rheumatol 2002; 14: 681-685.
22. Chen G, Grotendorst G, Eichholtz T, Khalil N. GM-CSF increases airway smooth muscle cell connective tissue expression by inducing TGF-beta receptors. Am J Physiol Lung Cell Mol Physiol 2003; 284: L548-L556.
23. Macklem PT. The physiology of small airways. Am J Respir Crit Care Med 1998; 157: S181-S183.
24. Kim WD, Eidelman DH, Izquierdo JL, Ghezzo H, Saetta MP, Cosio MG. Centrilobular and panlobular emphysema in smokers. Two distinct morphologic and functional entities. Am Rev Respir Dis 1991; 144: 1385-1390.
25. Hogg JC, Wright JL, Wiggs BR, Coxson HO, Opazo SA, Pare PD. Lung structure and function in cigarette smokers. Thorax 1994; 49: 473-478.
26. Nakano Y, Muro S, Sakai H, et al. Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function. Am J Respir Crit Care Med 2000; 162: 1102-1108.
27. Greaves IA, Colebatch HJ. Elastic behavior and structure of normal and emphysematous lungs post mortem. Am Rev Respir Dis 1980; 121: 127-136.
28. Pare PD, Brooks LA, Bates J, et al. Exponential analysis of the lung pressure-volume curve as a predictor of pulmonary emphysema. Am Rev Respir Dis 1982; 126: 54-61.
29. Pride NB, Milic-Emili J. Lung Mechanics. In: Calverley PMA, Macnee W, Rennard S, Pride NB, eds. Chronic Obstructive Pulmonary Disease. London, Arnold, 2003 (in press).
30. Van Brabandt H, Cauberghs M, Verbeken E, Moerman P, Lauweryns JM, Van de Woestijne KP. Partitioning of pulmonary impedance in excised human and canine lungs. J Appl Physiol 1983; 55: 1733-1742.
31. Verbeken EK, Cauberghs M, Mertens I, Lauweryns JM, Van de Woestijne KP. Tissue and airway impedance of excised normal, senile, and emphysematous lungs. J Appl Physiol 1992; 72: 2343-2353.
32. Yanai M, Sekizawa K, Ohrui T, Sasaki H, Takishima T. Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J Appl Physiol 1992; 72: 1016-1023.
33. Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977; 1: 1645-1648.
34. Peto R, Speizer FE, Cochrane AL, et al. The relevance in adults of air-flow obstruction, but not of mucus hypersecretion, to mortality from chronic lung disease. Results from 20 years of prospective observation. Am Rev Respir Dis 1983; 128: 491-500.
35. Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med 1996; 153: 1530-1535.
36. Vestbo J. Epidemiological studies in mucus hypersecretion. Novartis Found Symp 2002; 248: 3-12.
37. Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med 2001; 164: 358-364.
38. Saetta M, Turato G, Facchini FM, et al. Inflammatory cells in the bronchial glands of smokers with chronic bronchitis. Am J Respir Crit Care Med 1997; 156: 1633-1639.
39. + cells. Am J Respir Crit Care Med 2001; 164: 2220-2228.
40. Sommerhoff CP, Nadel JA, Basbaum CB, Caughey GH. Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J Clin Invest 1990; 85: 682-689.
41. Sommerhoff CP, Caughey GH, Finkbeiner WE, Lazarus SC, Basbaum CB, Nadel JA. Mast cell chymase: a potent secretagogue for airway gland serous cells. J Immunol 1989; 142: 2450-2455.
42. Witko-Sarsat V, Halbwachs-Mecarelli L, Schuster A, et al. Proteinase 3, a potent secretagogue in airways, is present in cystic fibrosis sputum. Am J Respir Cell Mol Biol 1999; 20: 729-736.
43. Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P. Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes. Thorax 1990; 45: 579-585.
44. Miravitlles M, Guerrero T, Mayordomo C, Sanchez-Agudo L, Nicolau F, Segu JL. Factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory COPD patients: a multiple logistic regression analysis. The EOLO Study Group. Respiration 2000; 67: 495-501.
45. Prescott E, Lange P, Vestbo J. Chronic mucus hypersecretion in COPD and death from pulmonary infection. Eur Respir J 1995; 8: 1333-1338.
46. Vestbo J, Lange P. Can GOLD Stage 0 provide information of prognostic value in chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2002; 166: 329-332.
47. Retamales I, Elliott WM, Meshi B, et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001; 164: 469-473.
48. Lacoste JY, Bousquet J, Chanez P. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis and chronic obstructive pulmonary disease. J Allergy Clin Immunol 1993; 92: 537-548.
49. Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med 1995; 152: 1666-1672.
50. Di Stefano A, Maestrelli P, Roggeri A, et al. Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am J Respir Crit Care Med 1994; 149: 803-810.
51. Sparrow D, Glynn RJ, Cohen M, Weiss ST. The relationship of the peripheral leukocyte count and cigarette smoking to pulmonary function among adult men. Chest 1984; 86: 383-386.
52. Stanescu D, Sanna A, Veriter C, et al. Airways obstruction, chronic expectoration and rapid decline in FEV1 in smokers are associated with increased levels of sputum neutrophils. Thorax 1996; 51: 267-271.
53. Terashima T, Wiggs B, English D, Hogg JC, van Eeden SF. Phagocytosis of small carbon particles (PM10) by alveolar macrophages stimulates the release of polymorphonuclear leukocytes from bone marrow. Am J Respir Crit Care Med 1997; 155: 1441-1447.
54. Macnee W, Wiggs B, Belzberg AS, Hogg JC. The effect of cigarette smoking on neutrophil kinetics in human lungs. N Engl J Med 1989; 321: 924-928.
55. Keatings VM, Barnes PJ. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma and normal subjects. Am J Respir Crit Care Med 1997; 155: 449-453.
56. Yamamoto C, Yoneda T, Yoshikawa M, et al. Airway inflammation in COPD assessed by sputum levels of interleukin-8. Chest 1997; 112: 505-510.
57. Peleman RA, Rytila PH, Kips JC, Joos GF, Pauwels RA. The cellular composition of induced sputum in chronic obstructive pulmonary disease. Eur Respir J 1999; 13: 839-843.
58. Richards GA, Theron AJ, Van der Merwe CA, Anderson R. Spirometric abnormalities in young smokers correlate with increased chemiluminescence responses of activated blood phagocytes. Am Rev Respir Dis 1989; 139: 181-187.
59. Condliffe AM, Kitchen E, Chilvers ER. Neutrophil priming: pathophysiological consequences and underlying mechanisms. Clin Sci (Lond) 1998; 94: 461-471.
60. Noguera A, Batle S, Miralles C, et al. Enhanced neutrophil response in chronic obstructive pulmonary disease. Thorax 2001; 56: 432-437.
61. Traves SL, Culpitt S, Russell REK, Barnes PJ, Donnelly LE. Elevated levels of the chemokines GRO-α and MCP-1 in sputum samples from COPD patients. Thorax 2002; 57: 590-595.
62. 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.
63. Bazzoni F, Cassatella MA, Rossi F, Ceska M, Dewald B, Baggiolini M. Phagocytosing neutrophils produce and release high amounts of the neutrophil-activating peptide 1/interleukin 8. J Exp Med 1991; 173: 771-774.
64. Hogg JC, Walker BA. Polymorphonuclear leucocyte traffic in lung inflammation. Thorax 1995; 50: 819-820.
65. Pettersen CA, Adler KB. Airways inflammation and COPD: epithelial-neutrophil interactions. Chest 2002; 121: 142S-150S.
66. Shapiro SD. The macrophage in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160: S29-S32.
67. Barnes PJ. Current and future therapies for airway mucus hypersecretion. Novartis Found Symp 2002; 248: 237-249.
68. Meshi B, Vitalis TZ, Ionescu D, et al. Emphysematous lung destruction by cigarette smoke. The effects of latent adenoviral infection on the lung inflammatory response. Am J Respir Cell Mol Biol 2002; 26: 52-57.
69. Punturieri A, Filippov S, Allen E, et al. Regulation of elastinolytic cysteine proteinase activity in normal and cathepsin K-deficient human macrophages. J Exp Med 2000; 192: 789-800.
70. Russell RE, Thorley A, Culpitt SV, et al. Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases. Am J Physiol Lung Cell Mol Physiol 2002; 283: L867-L873.
71. Russell RE, Culpitt SV, DeMatos C, 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 2002; 26: 602-609.
72. Lim S, Roche N, Oliver BG, Mattos W, Barnes PJ, Fan CK. Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers regulation by interleukin-10. Am J Respir Crit Care Med 2000; 162: 1355-1360.
73. Di Stefano A, Caramori G, Capelli A, et al. Increased expression of NF-κB in bronchial bioipsies from smokers and patients with COPD. Eur Respir J 2002; 20: 556-563.
74. Caramori G, Romagnoli M, Casolari P, et al. Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax 2003; 58: 348-351.
75. Capelli A, Di Stefano A, Gnemmi I, et al. Increased MCP-1 and MIP-1β in bronchoalveolar lavage fluid of chronic bronchitis. Eur Respir J 1999; 14: 160-165.
76. de Boer WI, Sont JK, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J Pathol 2000; 190: 619-626.
77. Traves SL, Smith SJ, Barnes PJ, Donnelly LE. Increased migration of monocytes from COPD patients towards GROα is not mediated by an increase in CXCR2 receptor expression. Am J Resp Crit Care Med: 2003: A824.
78. 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.
79. Tomita K, Caramori G, Lim S, et al. Increased p21CIP1/WAF1 and B cell lymphoma leukemia-xL expression and reduced apoptosis in alveolar macrophages from smokers. Am J Respir Crit Care Med 2002; 166: 724-731.
80. Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 1997; 155: 542-548.
81. Culpitt SV, Nightingale JA, Barnes PJ. 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 1999; 160: 1635-1639.
82. Culpitt SV, Rogers DF, Shah P, et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167: 24-31.
83. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001; 15: 1100-1102.
84. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits IL-1b-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 2000; 20: 6891-6903.
85. Ito K, Lim S, Caramori G, et al. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 2002; 99: 8921-8926.
86. Donnelly LE, Jones GE, Newton R, Barnes PJ. The anti-inflammatory action of resveratrol on human airway epithelial cells is not mediated via estrogen or glucocorticosteroid receptors. Am J Resp Crit Care Med 2003; 165: A614.
87. Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RA, Henson PM. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 2000; 405: 85-90.
88. Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 2002; 109: 41-50.
89. Vandivier RW, Fadok VA, Hoffmann PR, et al. Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 2002; 109: 661-670.
90. Majo J, Ghezzo H, Cosio MG. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Respir J 2001; 17: 946-953.
91. 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.
92. O'Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1. Am J Respir Crit Care Med 1997; 155: 852-857.
93. Vukmanovic-Stejic M, Vyas B, Gorak-Stolinska P, Noble A, Kemeny DM. Human Tel and Tc2/Tc0 CD8 T-cell clones display distinct cell surface and functional phenotypes. Blood 2000; 95: 231-240.
94. Leckie MJ, Jenkins GR, Khan J, et al. Sputum T lymphocytes in asthma, COPD and healthy subjects have the phenotype of activated intraepithelial T cells (CD69+ CD103+). Thorax 2003; 58: 23-29.
95. de Jong JW, Belt-Gritter B, Koeter GH, Postma DS. Peripheral blood lymphocyte cell subsets in subjects with chronic obstructive pulmonary disease: association with smoking, IgE and lung function. Respir Med 1997; 91: 67-76.
96. Kim WD, Kim WS, Koh Y, et al. Abnormal peripheral blood T-lymphocyte subsets in a subgroup of patients with COPD. Chest 2002; 122: 437-444.
97. Majori M, Corradi M, Caminati A, Cacciani G, Bertacco S, Pesci A. Predominant TH1 cytokine pattern in peripheral blood from subjects with chronic obstructive pulmonary disease. J Allergy Clin Immunol 1999; 103: 458-462.
98. Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med 2000; 109: 288-295.
99. Cosio MG, Majo J, Cosio MG. Inflammation of the airways and lung parenchyma in COPD: role of T cells. Chest 2002; 121: 160S-165S.
100. Prieto A, Reyes E, Bernstein ED, et al. Defective natural killer and phagocytic activities in chronic obstructive pulmonary disease are restored by glycophosphopeptical (inmunoferon). Am J Respir Crit Care Med 2001; 163: 1578-1583.
101. Zeidel A, Beilin B, Yardeni I, Mayburd E, Smirnov G, Bessler H. Immune response in asymptomatic smokers. Acta Anaesthesiol Scand 2002; 46: 959-964.
102. Hashimoto S, Kobayashi A, Kooguchi K, Kitamura Y, Onodera H, Nakajima H. Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome. Am J Respir Crit Care Med 2000; 161: 237-243.
103. Takubo Y, Guerassimov A, Ghezzo H, et al. Alpha1-antitrypsin determines the pattern of emphysema and function in tobacco smoke-exposed mice: parallels with human disease. Am J Respir Crit Care Med 2002; 166: 1596-1603.
104. Turato G, Zuin R, Saetta M. Pathogenesis and pathology of COPD. Respiration 2001; 68: 117-128.
105. Brightling CE, 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.
106. Papi A, Romagnoli M, Baraldo S, 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 2000; 162: 1773-1777.
107. Saetta M, Distefano A, Maestrelli P, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Resp Crit Care Med 1994; 150: 1646-1652.
108. Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia and expression of interieukin-5 protein in asthma and in exacerbations of chronic bronchitis. Clin Exp Allergy 1996; 26: 766-774.
109. Liu H, Lazarus SC, Caughey GH, Fahy JV. Neutrophil elastase and elastase-rich cystic fibrosis sputum degranulate human cosinophils in vitro. Am J Physiol 1999; 276: L28-L34.
110. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767-811.
111. Holt PG, Stumbles PA. Regulation of immunologic homeostasis in peripheral tissues by dendritic cells: the respiratory tract as a paradigm. J Allergy Clin Immunol 2000; 105: 421-429.
112. Huang Q, Liu D, Majewski P, et al. The plasticity of dendritic cell responses to pathogens and their components. Science 2001; 294: 870-875.
113. Francus T, Klein RF, Staiano-Coico L, Becker CG, Siskind GW. Effects of tobacco glycoprotein (TGP) on the immune system. II. TGP stimulates the proliferation of human T cells and the differentiation of human B cells into Ig secreting cells. J Immunol 1988; 140: 1823-1829.
114. Zeid NA, Muller HK. Tobacco smoke induced lung granulomas and tumors: association with pulmonary Langerhans cells. Pathology 1995; 27: 247-254.
115. Casolaro MA, Bernaudin JF, Saltini C, Ferrans VJ, Crystal RG. Accumulation of Langerhans' cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking. Am Rev Respir Dis 1988; 137: 406-411.
116. Soler P, Moreau A, Basset F, Hance AJ. Cigarette smoking-induced changes in the number and differentiated state of pulmonary dendritic cells/Langerhans cells. Am Rev Respir Dis 1989; 139: 1112-1117.
117. Tazi A, Soler P, Hance AJ. Adult pulmonary Langerhans' cell histiocytosis. Thorax 2000; 55: 405-416.
118. Tazi A, Moreau J, Bergeron A, Dominique S, Hance AJ, Soler P. Evidence that Langerhans cells in adult pulmonary Langerhans cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment. J Immunol 1999; 163: 3511-3515.
119. D'Hulst A, Vermeulen KY, Pauwels RA. Cigarette smoke exposure causes increase in pulmonary dendritic cells. Am J Respir Crit Care Med 2002; 164: A604.
120. Mio T, Romberger DJ, Thompson AB, Robbins RA, Heires A, Rennard SI. Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells. Am J Respir Crit Care Med 1997; 155: 1770-1776.
121. Hellermann GR, Nagy SB, Kong X, Lockey RF, Mohapatra SS. Mechanism of cigarette smoke condensate-induced acute inflammatory response in human bronchial epithelial cells. Respir Res 2002; 3: 22.
122. Floreani AA, Wyatt TA, Stoner J, et al. Smoke and C5a induce airway epithelial ICAM-1 and cell adhesion. Am J Respir Cell Mol Biol 2003 (in press).
123. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000; 106: 1311-1319.
124. Adler KB, Li Y. Airway epithelium and mucus: intracellular signaling pathways for gene expression and secretion. Am J Respir Cell Mol Biol 2001; 25: 397-400.
125. Aarbiou J, Rabe KF, Hiemstra PS. Role of defensins in inflammatory lung disease. Ann Med 2002; 34: 96-101.
126. Pilette C, Ouadrhiri Y, Godding V, Vaerman JP, Sibille Y. Lung mucosal immunity: immunoglobulin-A revisited. Eur Respir J 2001; 18: 571-588.
127. Demoly P, Simony-Lafontaine J, Chanez P, et al. Cell proliferation in the bronchial mucosa of asthmatics and chronic bronchitics. Am J Respir Crit Care Med 1994; 150: 214-217.
128. Franklin WA, Veve R, Hirsch FR, Helfrich BA, Bunn PA, Jr. Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol 2002; 29: 3-14.
129. Repine JE, Bast A, Lankhorst I. Oxidative stress in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997; 156: 341-357.
130. Macnee W. Oxidative stress and lung inflammation in airways disease. Eur J Pharmacol 2001; 429: 195-207.
131. Henricks PA, Nijkamp FP. Reactive oxygen species as mediators in asthma. Pulm Pharmacol Ther 2001; 14: 409-420.
132. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol 1996; 271: C1432-C1437.
133. Morrow JD. The isoprostanes: their quantification as an index of oxidant stress status in vivo. Drug Metab Rev 2000; 32: 377-385.
134. 2a, a novel noncyclooxygenase derived prostaglandin, is a potent constrictor of guinea-pig and human airways. Am J Respir Crit Care Med 1996; 153: 590-596.
135. Okazawa A, Kawikova I, Cui ZH, Skoogh BE, Lotvall J. 8-Epi-PGF2alpha induces airflow obstruction and airway plasma exudation in vivo. Am J Respir Crit Care Med 1997; 155: 436-441.
136. Janssen LJ. Isoprostanes: an overview and putative roles in pulmonary pathophysiology. Am J Physiol Lung Cell Mol Physiol 2001; 280: L1067-L1082.
137. van der Viet A, Eiserich JP, Shigenaga MK, Cross CE. Reactive nitrogen species and tyrosine nitration in the respiratory tract: epiphenomena or a pathobiologic mechanism of disease? Am J Respir Crit Care Med 1999; 160: 1-9.
138. Eiserich JP, Hristova M, Cross CE, et al. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 1998; 391: 393-397.
139. Gaut JP, Byun J, Tran HD, et al. Myeloperoxidase produces nitrating oxidants in vivo. J Clin Invest 2002; 109: 1311-1319.
140. Cantin AM, Fells GA, Hubbard RC, Crystal RG. Antioxidant macromolecules in the epithelial lining fluid of the normal human lower respiratory tract. J Clin Invest 1990; 86: 962-971.
141. Choi AM, 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.
142. Lim S, Groneberg D, Fischer A, et al. Expression of heme oxygenase isoenzymes 1 and 2 in normal and asthmatic airways. Effect of inhaled corticosteroids. Am J Respir Crit Care Med 2000; 162: 1912-1918.
143. Montuschi P, Kharitonov SA, Barnes PJ. Exhaled carbon monoxide and nitric oxide in COPD. Chest 2001; 120: 496-501.
144. Comhair SA, Erzurum SC. Antioxidant responses to oxidant-mediated lung diseases. Am J Physiol Lung Cell Mol Physiol 2002; 283: L246-L255.
145. Avissar N, Finkelstein JN, Horowitz S, et al. Extracellular glutathione peroxidase in human lung epithelial lining fluid and in lung cells. Am J Physiol 1996; 270: L173-L182.
146. Bowler RP, Crapo JD. Oxidative stress in airways: is there a role for extracellular superoxide dismutase? Am J Respir Crit Care Med 2002; 166: S38-S43.
147. Barnes PJ, Karin M. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. New Engl J Med 1997; 336: 1066-1071.
148. Janssen-Heininger YM, Poynter ME, Baeuerle PA. Recent advances towards understanding redox mechanisms in the activation of nuclear factor κB. Free Radic Biol Med 2000; 28: 1317-1327.
149. Adcock IM, Brown CR, Kwon OJ, Barnes PJ. Oxidative stress induces NF-κB DNA binding and inducible NOS mRNA in human epithelial cells. Biochem Biophys Res Commun 1994; 199: 1518-1524.
150. Rusznak C, Devalia JL, Sapsford RJ, Davies RJ. Ozone-induced mediator release from human bronchial epithelial cells in vitro and the influence of nedocromil sodium. Eur Respir J 1996; 9: 2298-2305.
151. Tomita K, Barnes PJ, Adcock IM. The effect of oxidative stress on histone acetylation and IL-8 release. Biochem Biophys Res Comm 2003; 301: 572-577.
152. Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J Biochem Mol Biol 2003; 36: 95-109.
153. Xanthoudakis S, Curran T. Redox regulation of AP-1: a link between transcription factor signaling and DNA repair. Adv Exp Med Biol 1996; 387: 69-75.
154. Devalia JL, Bayram H, Rusznak C, et al. Mechanisms of pollution-induced airway disease: in vitro studies in the upper and lower airways. Allergy 1997; 52: 45-5; 57-58.
155. Ogura M, Kitamura M. Oxidant stress incites spreading of macrophages via extracellular signal-regulated kinases and p38 mitogen-activated protein kinase. J Immunol 1998; 161: 3569-3574.
156. Forman HJ, Torres M. Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. Am J Respir Crit Care Med 2002; 166: S4-S8.
157. Pryor WA, Stone K. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann N Y Acad Sci 1993; 686: 12-27.
158. Britton JR, Pavord ID, Richards KA, et al. Dietary antioxidant vitamin intake and lung function in the general population. Am J Respir Crit Care Med 1995; 151: 1383-1387.
159. Schunemann HJ, Freudenheim JL, Grant BJ. Epidemiologic evidence linking antioxidant vitamins to pulmonary function and airway obstruction. Epidemiol Rev 2001; 23: 248-267.
160. Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 2001; 163: 1693-1772.
161. Montuschi P, Barnes PJ. Analysis of exhaled breath condensate for monitoring airway inflammation. Trends Pharmacol Sci 2002; 23: 232-237.
162. Paredi P, Kharitonov SA, Barnes PJ. Analysis of expired air for oxidation products. Am J Respir Crit Care Med 2002; 166: S31-S37.
163. Dekhuijzen PNR, Aben KHH, Dekker I, et al. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 154: 813-816.
164. Nowak D, Kasielski M, Antczak A, Pietras T, Bialasiewicz P. Increased content of thiobarbituric acid-reactive substances and hydrogen peroxide in the expired breath condensate of patients with stable chronic obstructive pulmonary disease: no significant effect of cigarette smoking. Respir Med 1999; 93: 389-396.
165. Montuschi P, Collins JV, Ciabattoni G, 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 2000; 162: 1175-1177.
166. Biernacki WA, Kharitonov SA, Barnes PJ. Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD. Thorax 2003; 58: 294-298.
167. 2a-III, an index of oxidant stress. Am J Respir Crit Care Med 1998; 158: 1709-1714.
168. Rahman I, Morrison D, Donaldson K, Macnee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med 1996; 154: 1055-1060.
169. Rahman I, van Schadewijk AA, Crowther AJ, et al. 4-Hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166: 490-495.
170. Taggart C, Cervantes-Laurean D, Kim G, et al. Oxidation of either methionine 351 or methionine 358 in α1-antitrypsin causes loss of anti-neutrophil elastase activity. J Biol Chem 2000; 275: 27258-27265.
171. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999; 353: 1819-1823.
172. Pauwels RA, Lofdahl CG, Laitinen LA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999; 340: 1948-1953.
173. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen T. 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 2000; 320: 1297-1303.
174. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. New Engl J Med 2000; 343: 1902-1909.
175. Hutchison KA, Matic G, Meshinchi S, Bresnick EH, Pratt WB. Redox manipulation of DNA binding activity and BuGR epitope reactivity of the glucocorticoid receptor. J Biol Chem 1991; 266: 10505-10509.
176. Okamoto K, Tanaka H, Ogawa H, et al. Redox-dependent regulation of nuclear import of the glucocorticoid receptor. J Biol Chem 1999; 274: 10363-10371.
177. Barnes PJ, Adcock IM. How corticosteroid switch off inflammation in asthma. Ann Int Med 2003 (in press).
178. Ito K, Watanabe S, Kharitonov S, Hanazawa T, Adcock IM, Barnes PJ. Histone deacetylase activity and gene expression in COPD patients. Eur Respir J 2001; 18: 316S.
179. Gotoh Y, Cooper JA. Reactive oxygen species- and dimerization-induced activation of apoptosis signal-regulating kinase 1 in tumor necrosis factor-a signal transduction. J Biol Chem 1998; 273: 17477-17482.
180. Gottlieb DJ, Stone PJ, Sparrow D, et al. Urinary desmosine excretion in smokers with and without rapid decline of lung function: the Normative Aging Study. Am J Respir Crit Care Med 1996; 154: 1290-1295.
181. Stockley RA. Proteases and antiproteases. Novartis Found Symp 2001; 234: 189-199.
182. Senior RM, Tegner H, Kuhn C, Ohlsson K, Starcher BC, Pierce JA. The induction of pulmonary emphysema with human leukocyte elastase. Am Rev Respir Dis 1977; 116: 469-475.
183. Damiano VV, Tsang A, Kucich U, et al. Immunolocalization of elastase in human emphysematous lungs. J Clin Invest 1986; 78: 482-493.
184. Owen CA, Campbell MA, Boukedes SS, Campbell EJ. Cytokines regulate membrane-bound leukocyte elastase on neutrophils: a novel mechanism for effector activity. Am J Physiol 1997; 272: L385-L393.
185. Takeyama K, Agusti C, Ueki I, Lausier J, Cardell LO, Nadel JA. Neutrophil-dependent goblet cell degranulation: role of membrane-bound elastase and adhesion molecules. Am J Physiol 1998; 275: L294-L302.
186. Voynow JA, Young LR, Wang Y, Horger T, Rose MC, Fischer BM. Neutrophil elastase increases MUC5AC mRNA and protein expression in respiratory epithelial cells. Am J Physiol 1999; 276: L835-L843.
187. Fischer BM, Voynow JA. Neutrophil elastase induces MUC5AC gene expression in airway epithelium via a pathway involving reactive oxygen species. Am J Respir Cell Mol Biol 2002; 26: 447-452.
188. Nakamura H, Yoshimura K, McElvaney NG, Crystal RG. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J Clin Invest 1992; 89: 1478-1484.
189. Le Barillec K, Si-Tahar M, Balloy V, Chignard M. Proteolysis of monocyte CD14 by human leukocyte elastase inhibits lipopolysaccharide-mediated cell activation. J Clin Invest 1999; 103: 1039-1046.
190. Belaaouaj A, McCarthy R, Baumann M, et al. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat Med 1998; 4: 615-618.
191. Shapiro SD. Neutrophil elastase: path clearer, pathogen killer, or just pathologic? Am J Respir Cell Mol Biol 2002; 26: 266-268.
192. Ohbayashi H. Neutrophil elastase inhibitors as treatment for COPD. Expert Opin Investig Drugs 2002; 11: 965-980.
193. Wright JL, Farmer SG, Churg A. Synthetic serine elastase inhibitor reduces cigarette smoke-induced emphysema in guinea pigs. Am J Respir Crit Care Med 2002; 166: 954-960.
194. Luisetti M, Sturani C, Sella D, et al. MR889, a neutrophil elastase inhibitor, in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled clinical trial. Eur Respir J 1996; 9: 1482-1486.
195. Gorrini M, Lupi A, Viglio S, et al. Inhibition of human neutrophil elastase by erythromycin and flurythromycin, two macrolide antibiotics. Am J Respir Cell Mol Biol 2001; 25: 492-499.
196. Goswami SK, Kivity S, Marom Z. Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro. Am Rev Respir Dis 1990; 141: 72-78.
197. Campbell EJ, Campbell MA, Owen CA. Bioactive proteinase 3 on the cell surface of human neutrophils: quantification, catalytic activity, and susceptibility to inhibition. J Immunol 2000; 165: 3366-3374.
198. Duranton J, Bieth JG. Inhibition of proteinase 3 by α1-antitrypsin in vitro predicts very fast inhibition in vivo. Am J Respir Cell Mol Biol 2003; 29: 57-61.
199. Turk V, Turk B, Turk D. Lysosomal cysteine proteases: facts and opportunities. EMBO J 2001; 20: 4629-4633.
200. Chapman HA, Riese RJ, Shi GP. Emerging roles for cysteine proteases in human biology. Annu Rev Physiol 1997; 59: 63-88.
201. 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.
202. 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.
203. Reddy VY, Zhang QY, Weiss SJ. Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages. Proc Natl Acad Sci USA 1995; 92: 3849-3853.
204. Linnevers C, Smeekens SP, Bromme D. Human cathepsin W, a putative cysteine protease predominantly expressed in CD8+ T-lymphocytes. FEBS Lett 1997; 405: 253-259.
205. 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.
206. Shapiro SD, Senior RM. Matrix metalloproteinases. Matrix degradation and more. Am J Respir Cell Mol Biol 1999; 20: 1100-1102.
207. Finlay GA, O'Driscoll LR, Russell KJ, et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med 1997; 156: 240-247.
208. Betsuyaku T, Nishimura M, Takeyabu K, et al. Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema. Am J Respir Crit Care Med 1999; 159: 1985-1991.
209. Ohnishi K, Takagi M, Kurokawa Y, Satomi S, Konttinen YT. Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab Invest 1998; 78: 1077-1087.
210. Imai K, Dalal SS, Chen ES, et al. Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema. Am J Respir Crit Care Med 2001; 163: 786-791.
211. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage metalloelastase for cigarette smoke-induced emphysema in mice. Science 1997; 277: 2002-2004.
212. Morris DG, Huang X, Kaminski N, et al. Loss of integrin avb6-mediated TGF-b activation causes MMP12-dependent emphysema. Nature 2003; 422: 169-173.
213. Lanone S, Zheng T, Zhu Z, et al. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. J Clin Invest 2002; 110: 463-474.
214. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000; 14: 163-176.
215. Dallas SL, Rosser JL, Mundy GR, Bonewald LF. Proteolysis of latent transforming growth factor-β (TGF-β)-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-b from bone matrix. J Biol Chem 2002; 277: 21352-21360.
216. Rooney CP, Taggart C, Coakley R, McElvaney NG, O'Neill SJ. Anti-proteinase 3 antibody activation of neutrophils can be inhibited by α1-antitrypsin. Am J Respir Cell Mol Biol 2001; 24: 747-754.
217. Mahadeva R, Lomas DA. Genetics and respiratory disease. 2. Alpha 1-antitrypsin deficiency, cirrhosis and emphysema. Thorax 1998; 53: 501-505.
218. Carrell RW, Lomas DA. α1-antitrypsin deficiency - a model for conformational diseases. N Engl J Med 2002; 346: 45-53.
219. Lomas DA, Mahadeva R. α1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest 2002; 110: 1585-1590.
220. Carp H, Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis 1978; 118: 617-621.
221. Vogelmeier C, Hubbard RC, Fells GA, et al. Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor. J Clin Invest 1991; 87: 482-488.
222. Taggart CC, Lowe GJ, Greene CM, et al. Cathepsin B, L, and S cleave and inactivate secretory leucoprotease inhibitor. J Biol Chem 2001; 276: 33345-33352.
223. Jin FY, Nathan C, Radzioch D, Ding A. Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell 1997; 88: 417-426.
224. Zhang Y, DeWitt DL, McNeely TB, Wahl SM, Wahl LM. Secretory leukocyte protease inhibitor suppresses the production of monocyte prostaglandin H synthase-2, prostaglandin E2 and matrix metalloproteinases. J Clin Invest 1997; 99: 894-900.
225. Taggart CC, Greene CM, McElvaney NG, O'Neill S. Secretory leucoprotease inhibitor prevents lipopolysaccharide-induced IκBα degradation without affecting phosphorylation or ubiquitination. J Biol Chem 2002; 277: 33648-33653.
226. Sallenave JM. The role of secretory leukocyte proteinase inhibitor and elafin (elastase-specific inhibitor/skin-derived antileukoprotease) as alarm antiproteinases in inflammatory lung disease. Respir Res 2000; 1: 87-92.
227. Ishii T, Matsuse T, Teramoto S, et al. Association between a1-antichymotrypsin polymorphism and susceptibility to chronic obstructive pulmonary disease. Eur J Clin Invest 2000; 30: 543-548.
228. Cawston T, Carrere S, Catterall J, et al. Matrix metalloproteinases and TIMPs: properties and implications for the treatment of chronic obstructive pulmonary disease. Novartis Found Symp 2001; 234: 205-218.
229. Hirano K, Sakamoto T, Uchida Y, et al. Tissue inhibitor of metalloproteinases-2 gene polymorphisms in chronic obstructive pulmonary disease. Eur Respir J 2001; 18: 748-752.
230. Barnes PJ. Molecular genetics of chronic obstructive pulmonary disease. Thorax 1999; 54: 245-252.
231. Lomas DA, Silverman EK. The genetics of chronic obstructive pulmonary disease. Respir Res 2001; 2: 20-26.
232. Hogg JC. Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med 2001; 164: S71-S75.
233. Gilmour PS, Rahman I, Hayashi S, Hogg JC, Donaldson K, Macnee W. Adenoviral E1A primes alveolar epithelial cells to PM(10)-induced transcription of interleukin-8. Am J Physiol Lung Cell Mol Physiol 2001; 281: L598-L606.
234. Higashimoto Y, Elliott WM, Behzad AR, et al. Inflammatory mediator mRNA expression by adenovirus E1A-transfected bronchial epithelial cells. Am J Respir Crit Care Med 2002; 166: 200-207.
235. 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.
236. Rutgers SR, Postma DS, ten Hacken NH, et al. Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax 2000; 55: 12-18.
237. Loppow D, Schleiss MB, Kanniess F, Taube C, Jorres RA, Magnussen H. In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation. Respir Med 2001; 95: 115-121.
238. Meagher LC, Cousin JM, Seekl JR, Haslett C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol 1996; 156: 4422-4428.
239. Nightingale JA, Rogers DF, Chung KF, Barnes PJ. No effect of inhaled budesonide on the response to inhaled ozone in normal subjects. Am J Respir Crit Care Med 2000; 161: 479-486.
240. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research Group. Am J Respir Crit Care Med 1996; 153: 1802-1811.
241. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimou J. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998; 351: 773-780.
242. Yamada K, Elliott WM, Brattsand R, Valeur A, Hogg JC, Hayashi S. Molecular mechanisms of decreased steroid responsiveness induced by latent adenoviral infection in allergic lung inflammation. J Allergy Clin Immunol 2002; 109: 35-42.
243. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999; 340: 1941-1947.
244. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet 1999; 354: 456-460.
245. Wedzicha JA. Exacerbations: etiology and pathophysiologic mechanisms. Chest 2002; 121: 136S-141S.
246. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 1418-1422.
247. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002; 57: 847-852.
248. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164: 1618-1623.
249. Donaldson GC, Seemungal T, Jeffries DJ, Wedzicha JA. Effect of temperature on lung function and symptoms in chronic obstructive pulmonary disease. Eur Respir J 1999; 13: 844-849.
250. Crooks SW, Bayley DL, Hill SL, Stockley RA. Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur Respir J 2000; 15: 274-280.
251. Aaron SD, Angel JB, Lunau M, et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 349-355.
252. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 2000; 55: 114-120.
253. Gompertz S, Bayley DL, Hill SL, Stockley RA. Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD. Thorax 2001; 56: 36-41.
254. Gompertz S, O'Brien C, Bayley DL, Hill SL, Stockley RA. Changes in bronchial inflammation during acute exacerbations of chronic bronchitis. Eur Respir J 2001; 17: 1112-1119.
255. Patel IS, Seemungal TA, Wilks M, Lloyd-Owen SJ, Donaldson GC, Wedzicha JA. Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations. Thorax 2002; 57: 759-764.
256. Maziak W, Loukides S, Culpitt S, Sullivan P, Kharitonov SA, Barnes PJ. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 998-1002.
257. Agusti AG, Villaverde JM, Togores B, Bosch M. Serial measurements of exhaled nitric oxide during exacerbations of chronic obstructive pulmonary disease. Eur Respir J 1999; 14: 523-528.
258. Sethi S, Murphy TF. Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art review. Clin Microbiol Rev 2001; 14: 336-363.
259. Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002; 347: 465-471.
260. van Alphen L, Jansen HM, Dankert J. Virulence factors in the colonization and persistence of bacteria in the airways. Am J Respir Crit Care Med 1995; 151: 2094-2099.
261. Moller LV, Timens W, van der BW, et al. Haemophilus influenzae in lung explants of patients with end-stage pulmonary disease. Am J Respir Crit Care Med 1998; 157: 950-956.
262. van Schilfgaarde M, Eijk P, Regelink A, et al. Haemophilus influenzae localized in epithelial cell layers is shielded from antibiotics and antibody-mediated bactericidal activity. Microb Pathog 1999; 26: 249-262.
263. Bresser P, Out TA, van Alphen L, Jansen HM, Lutter R. Airway inflammation in nonobstructive and obstructive chronic bronchitis with chronic Haemophilus influenzae airway infection. Comparison with noninfected patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162: 947-952.
264. Gorter AD, Eijk PP, van Wetering S, Hiemstra PS, Dankert J, van Alphen L. Stimulation of the adherence of Haemophilus influenzae to human lung epithelial cells by antimicrobial neutrophil defensins. J Infect Dis 1998; 178: 1067-1074.
265. Barnes PJ. New treatments for COPD. Nature Rev Drug Disc 2002; 1: 437-445.