Perspektiven der antiinflammatorischen Pharmakotherapie der COPD: Neutrophile Granulozyten im Fokus

Zusammenfassung

Die bronchiale Entzündung der chronisch-obstruktiven Lungenerkrankung (COPD) ist durch eine Akkumulation neutrophiler Granulozyten in den Atemwegen betroffener Patienten gekennzeichnet. Gegenwärtig verfügbare Therapien haben jedoch einen allenfalls minimalen Einfluss auf neutrophile Entzündungsvorgänge. Daher werden große Anstrengungen unternommen, neue antiinflammatorische Therapieansätze der COPD zu entwickeln. Zahlreiche solcher Ansätze zielen auf die Reduktion von Neutrophilen in der Lunge bzw. Unterdrückung neutrophiler Effektorfunktionen. In der vorliegenden Übersicht werden aktuelle Forschungsergebnisse und daraus abgeleitete Therapiekonzepte zur inflammatorischen Pathogenese der COPD dargestellt. Insbesondere werden offene Fragen zum Entwurf adäquater klinischer Prüfungen, Möglichkeit und Grenzen geeigneter Zielparameter, sowie Aspekte zu Risiken und Verträglichkeit anti-neutrophiler Therapien kritisch beleuchtet.

Abstract

Inflammation in COPD is characterized by an increased presence and activation of airway neutrophils. However, since currently available treatment options have only limited effects on neutrophilic airway inflammation, great efforts are undertaken to develop novel therapies targeting the neutrophilic component of inflammation in COPD. The present review discusses the rationale for anti-neutrophilic treatment in COPD and provides a critical overview of recent developments in drug therapy. Moreover, open questions and limitations of clinical trials including choice of adequate outcome parameters for proof-of-concept studies with putative anti-neutrophilic drugs and potential safety issues are summarized.

Literatur

• 1 Stockley R A. Neutrophils and the pathogenesis of COPD.  Chest. 2002;  121 151S-155S
• 2 Thurlbeck W M. Pathology of chronic obstructive pulmonary disease.  Clin Chest Med. 1990;  11 389-404
• 3 Di Stefano A, Capelli A, Lusuardi M. et al . Severity of airflow limitiation is associated with severity of airway inflammation in smokers.  Am J Respir Crit Care Med. 1998;  158 1277-1285
• 4 Burge P S, Calverley P MA, Jones P W. et al . Randomised double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary diease: the ISOLDE trial.  Br Med J. 2000;  320 1297-1303
• 5 Paggiaro P L, Dahle R, Barman I. et al . Multicenter randomised placebo-controlled trial of inhaled fluticasone proprionate in patients with chronic obstructive pulmonary disease.  Lancet. 1998;  351 773-780
• 6 Vestbo J, Sorensen T IA, Lange P. et al . Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial.  Lancet. 1999;  353 1819-1823
• 7 Lung Health Study Group . Effect of Inhaled Triamcinolone on the Decline in Pulmonary Function in Chronic Obstructive Pulmonary Disease.  N Engl J Med. 2000;  343 1902-1909
• 8 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. The lung health study.  JAMA. 1994;  272 1497-1505
• 9 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. 200;  55 12-18
• 10 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
• 11 Bhowmik A, Seemungal T AR, Sapsford R J. et al . Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations.  Thorax. 2000;  55 114-120
• 12 Stockley R A. Neutrophils and protease/antiprotease imbalance.  Am J Respir Crit Care Med. 1999;  160 S49-S52
• 13 Nadel J A. Role of neutrophil elastase in hypersecretion during COPD exacerbations, and proposed therapies.  Chest. 2000;  117 386S-389S
• 14 Vestbo J, Prescott E, Lange D P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity.  Am J Respir Crit Care Med. 1996;  153 1530-1535
• 15 Maestrelli P, Calcagni P G, Saetta M. et al . Integrin upregulation on sputum neutrophils in smokers with chronic airway obstruction.  Am J Respir Crit Care Med. 1996;  154 1296-1300
• 16 Noguera A, Busquets X, Sauleda J. et al . Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 1998;  158 1664-1668
• 17 Noguera A, Batle S, Miralles C. et al . Enhanced neutrophil response in chronic obstructive pulmonary disease.  Thorax. 2001;  56 432-437
• 18 Burnett D, Chamba A, Hill S L. et al . Neutrophils from subjects with chronic obstructive lung disease show enhanced chemotaxis and extracellular proteolysis.  Lancet. 1987;  II (8567) 1043-1046
• 19 Aaron S D, Angel J B, 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
• 20 Qiu Y, Zhu J, Bandi V. et al . Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2003;  168 968-975
• 21 Yamamoto C, Yoneda T, Yoshikawa M. et al . Airway inflammation in COPD assessed by sputum levels of interleukin-8.  Chest. 1997;  112 505-510
• 22 Traves S L, Culpitt S V, Russell R E. et al . Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD.  Thorax. 2002;  57 590-595
• 23 Keatings V M, Collins P D, Scott D M. et al . 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
• 24 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. 1999;  160 893-898
• 25 Lim S N, Roche N, Oliver B G. et al . 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
• 26 Beeh K M, Beier J, Kornmann O. et al . Sputum matrixmetalloproteinase-9, tissue inhibitor of metalloproteinase-1, and their molar ratio in patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and healthy subjects.  Respir Med. 2003;  97 634-639
• 27 Finlay G A, Russell K J, McMahon K J. et al . Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients.  Thorax. 1997;  52 502-506
• 28 Keatings V M, Barnes P J. 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
• 29 Beeh K M, Beier J, Kornmann O. et al . Long-term repeatability of induced sputum inflammatory markers in stable, moderately severe COPD.  Chest. 2003;  123 778-783
• 30 Ichinose M, Sugiura H, Yamagata S. et al . Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways.  Am J Respir Crit Care Med. 2000;  162 701-706
• 31 Corradi M, Montuschi P, Donnelly L E. et al . Increased nitrosothiols in exhaled breath condensate in inflammatory airway diseases.  Am J Respir Crit Care Med. 2001;  163 854-858
• 32 Kanazawa H S, Shiraishi S, Hirata K. et al . Imbalance between levels of nitrogen oxides and peroxynitrite inhibitory activity in chronic obstructive pulmonary disease.  Thorax. 2003;  58 106-109
• 33 Beeh K M, Beier J, Koppenhoefer N. et al . Increased glutathione disulfide and nitrosothiols in COPD sputum supernatant.  Chest. 2004;  126 1116-1122
• 34 Montuschi P, Collins J V, 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
• 35 Morrison D, Rahman I, Lannan S. et al . Epithelial permeability, inflammation, and oxidant stress in the air spaces of smokers.  Am J Respir Crit Care Med. 1999;  159 473-479
• 36 McNulty C A, Symon F A, Wardlaw A J. Characterization of the integrin and activation steps mediating human eosinophil and neutrophil adhesion to chronically inflamed airway endothelium.  Am J Respir Cell Mol Biol. 1999;  20 1251-1259
• 37 Adams D H, Lloyd A R. Chemokines: leucocyte recruitment and activation cytokines.  Lancet. 1997;  349 490-495
• 38 Selby C, Drost E, Lannan S. et al . Neutrophil retention in the lungs of patients with chronic obstructive pulmonary disease.  Am Rev Respir Dis. 1991;  143 1359-1364
• 39 Lams B E, Sousa A R, Rees P J. et al . Immunopathology of the Small-Airway Submucosa in Smokers with and without Chronic Obstructive Pulmonary Disease.  Am J Respir Crit Care Med. 1998;  158 1518-1523
• 40 Pilette C, Godding V, Kiss R. et al . Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2001;  163 185-194
• 41 Baraldo S, Turato G, Badin C. et al . Neutrophilic infiltration within the airway smooth muscle in patients with COPD.  Thorax. 2004;  59 308-312
• 42 Keatings V M, Jatakanon A, Worsdell Y M. et al . Effects of inhaled and oral glucocorticosteroids on inflammatory indices in asthma and COPD.  Am J Respir Crit Care Med. 1997;  155 542-548
• 43 Culpitt S V, Maziak W, Loukidis S. et al . 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
• 44 Gonfalonieri M, Mainardi E, Della Porta R. Inhaled corticosteroids reduce neutrophilic bronchial inflammation in patients with chronic obstructive pulmonary disease.  Thorax. 1998;  53 583-585
• 45 Yildiz F, Kaur A C, Ilgazi A. et al . Inhaled corticosteroids may reduce neutrophilic inflammation in patients with stable chronic obstructive pulmonary disease.  Respiration. 2000;  67 71-76
• 46 Barnes P J, Ito K, Adcock I M. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase.  Lancet. 2004;  363 731-733
• 47 GOLD Executive Summary .Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2003 update. NIH Publication 2003: 1-42
• 48 Calotta F, Re F, Polentarutti N. et al . Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products.  Blood. 1992;  80 2012-2020
• 49 Drost E M, MacNee W. Potential role of IL-8, platelet-activating factor and TNF-alpha in the sequestration of neutrophils in the lung: effects on neutrophil deformability, adhesion receptor expression, and chemotaxis.  Eur J Immunol. 2002;  32 393-403
• 50 John M, Au B T, Jose P J. et al . Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2-cytokines and corticosteroids.  American Review of Respiratory and Cellular and Molecular Biology. 1998;  18 (1) 84-90
• 51 Beeh K M, Kornmann O, Buhl R. et al . Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4.  Chest. 2003;  123 1240-1247
• 52 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
• 53 Gibson P G, Simpson J L, Saltos N. Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8.  Chest. 2001;  119 1329-1336
• 54 Jatakanon A, Uasuf C, Maziak W. et al . Neutrophilic inflammation in severe persistent asthma.  Am J Respir Crit Care Med. 1999;  160 1532-1539
• 55 Richman-Eisenstat J B, Jorens P G, Hebert C A. et al . Interleukin-8: an important chemoattractant in sputum of patients with chronic inflammatory airway diseases.  Am J Physiol. 1993;  264 L413-L418
• 56 Beeh K M, Beier J, Kornmann O. et al . Neutrophilic inflammation in induced sputum of patients with idiopathic pulmonary fibrosis.  Sarc Vasc Diff Lung Dis. 2003;  20 138-143
• 57 DiGiovine B, Lynch J P, Martinez F J. et al . 1996. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8.  J Immunol. 1996;  157 4194-4202
• 58 Feldmann M, Brennan F M, Maini R N. Role of cytokines in rheumatoid arthritis.  Annu Rev Immunol. 1996;  14 397-440
• 59 Yuan A, Yang P C, Yu C J. et al . Interleukin-8 messenger ribonucleic acid expression correlates with tumor progression, tumor angiogenesis, patient survival, and timing of relapse in non-small-cell lung cancer.  Am J Respir Crit Care Med. 2000;  162 1957-1963
• 60 Yuan A, Yu C J, Luh K T. et al . Aberrant p53 expression correlates with expression of vascular endothelial growth factor mRNA and interleukin-8 mRNA and neoangiogenesis in non-small-cell lung cancer.  J Clin Oncol. 2002;  20 900-910
• 61 Huang S, Mills L, Mian B. et al . Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastases of human melanoma.  Am J Pathol. 2002;  161 125-134
• 62 Yang X D, Corvalan J R, Wang P. et al . 1999. Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states.  J Leukoc Biol. 1999;  66 401-410
• 63 Mahler D A, Huang S L, Tabrizi M. et al . Efficacy and Safety of a Monoclonal Antibody Recognizing Interleukin-8 in COPD: A Pilot Study.  Chest. 2004;  126 926-934
• 64 McColl S R, Clark-Lewis I. Inhibition of murine neutrophil recruitment in vivo by CXC chemokine receptor antagonists.  J Immunol. 1999;  163 2829-2835
• 65 White J R, Lee J M, Young P R. et al . Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration.  J Biol Chem. 1998;  273 10 095-10 098
• 66 Crooks S W, Stockley R A. Leukotriene B4.  Int J Biochem Cell Biol. 1998;  30 173-178
• 67 Martin T R, Pistorese B P, Chi E Y. et al . Effects of leukotriene B4 in the human lung: Recruitment of neutrophils into the alveolar spaces without a change in protein permeability.  J Clin Invest. 1989;  84 1609-1619
• 68 Seggev J S, Thornton W H, Edes T E. Serum leukotriene B4 levels in patients with obstructive pulmonary disease.  Chest. 1991;  99 289-291
• 69 Wardlaw A J, Hay H, Cromwell O. et al . Leukotrienes, LTC4 and LTB4, in bronchoalveolar lavage in bronchial asthma and other respiratory diseases.  J Allergy Clin Immunol. 1989;  84 19-26
• 70 Woolhouse I S, Bayley D L, Stockley R A. Sputum chemotactic activity in chronic obstructive pulmonary disease: effect of a1-antitrypsin deficiency and the role of leukotriene B4 and interleukin 8.  Thorax. 2002;  57 709-714
• 71 Biernacki W A, Kharitonov S A, Barnes P J. Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD.  Thorax. 2003;  58 294-298
• 72 Lee E, Lindo T, Jackson N. et al . Reversal of human neutrophil survival by leukotriene B4 receptor blockade and 5-lipoxygenase activating protein inhibitors.  Am J Respir Crit Care Med. 1999;  160 2079-2085
• 73 Gompertz S, Stockley R A. A randomized, placebo-controlled trial of a leukotriene synthesis inhibitor in patients with COPD.  Chest. 2002;  122 289-294
• 74 Silbaugh S A, Stengel P W, Cockerham S L. et al . Pharmacologic actions of the second generation leukotriene B4 receptor antagonist LY29311: in vivo pulmonary studies.  Naunyn Schmiedebergs Arch Pharmacol. 2000;  361 397-404
• 75 Evans D J, Barnes P J, Spaethe S M. et al . Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma.  Thorax. 1996;  51 1178-1184
• 76 Groenke L, Beeh K M, Wang J H. et al . LTB 019A, a leukotriene B4 receptor antagonist, has no effect on the levels of neutrophils, MPO, IL-8 and TNF-alpha in induced sputum of patients with COPD.  Am J Respir Crit Care Med. 2002;  165 A225
• 77 Dang B, Wiehler S, Patel K D. Increased PSGL-1 expression on granulocytes from allergic asthmatic subjects results in enhanced leukocyte recruitment under flow conditions.  J Leukoc Biol. 2002;  72 702-710
• 78 Lin S J, Chang L Y, Yan D C. et al . Decreased intercellular adhesion molecule-1 (CD54) and L-selectin (CD62L) expression on peripheral blood natural killer cells in asthmatic children with acute exacerbation.  Allergy. 2003;  58 67-71
• 79 Pettersen C A, Adler K B. Airways inflammation and COPD. Epithelial-neutrophil interactions.  Chest. 2002;  121 142S-150S
• 80 Abraham W M, Ahmed A, Sabater J R. et al . Selectin blockade prevents antigen-induced late bronchial responses and airway hyperresponsiveness in allergic sheep.  Am J Respir Crit Care Med. 1999;  159 1205-1214
• 81 Sanctis G T de, Wolyniec W W, Green F H. et al . 1997. Reduction of allergic airway responses in P-selectin-deficient mice.  J Appl Physiol. 1997;  83 681-687
• 82 Lukacs N W, John A, Berlin A. et al . E- and P-selectins are essential for the development of cockroach allergen-induced airway responses.  J Immunol. 2002;  169 2120-2125
• 83 Radi Z A, Brodgen K A, Dixon R A. et al . A selectin inhibitor decreases neutrophil infiltration during acute mannheimia haemolytica pneumonia.  Vet Pathol. 2002;  39 697-705
• 84 Kogan T P, Dupre B, Bui H. et al . Novel synthetic inhibitors of selectin-mediated cell adhesion: synthesis of 1,6-bis[3-(3-carboxymethylphenyl)-4-(2-alpha-D- mannopyranosyloxy)phenyl]hexane (TBC1269).  J Med Chem. 1998;  41 1099-1111
• 85 Davenpeck K L, Berens K L, Dixon R A. et al . 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. 2000;  105 769-775
• 86 Avila P C, Boushey H A, Wong H. et al . 2004. Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses.  Clin Exp Allergy. 2004;  34 77-84
• 87 Beeh K M, Beier J, Meyer M. et al . Bimosiamose, an inhaled small-molecule pan-selectin antagonist, attenuates late asthmatic reactions following allergen challenge in mild asthmatics: A randomized, double-blind, placebo-controlled clinical cross-over-trial.  Pulmonary Pharmacology and Therapeutics. 2005;  DOI: 10.1016/j.pubt.2005.07.004
• 88 Hu Y, Kiely J M, Szente B E. et al . E-selectin-dependent signaling via the mitogen-activated protein kinase pathway in vascular endothelial cells.  J Immunol. 2000;  165 2142-2148
• 89 Lorenzon P, Vedile E, Nardon E. et al . Endothelial cell E- and P-Selectin and vascular cell adhesion molecule-1 function as signalling receptors.  J Cell Biol. 1998;  142 1381-1391
• 90 Laudanna C, Constantin G, Baron P. et al . Sulfatides trigger increase of cytosolic free calcium and enhanced expression of tumor necrosis factor-alpha and interleukin-8 mRNA in human neutrophils.  J Biol Chem. 1994;  269 4021-4026
• 91 Bouma M G, Jeunhomme T M, Boyle D L. et al . Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors.  J Immunol. 1997;  158 5400-5408
• 92 Fozard J R, Ellis K M, Villela Dantas M F. et al . Effects of CGS 21680, a selective adenosine A2A receptor agonist, on allergic airways inflammation in the rat.  Eur J Pharmacol. 2002;  438 183-188
• 93 Luijk B, Berge M van den, Kerstjens H AM. et al . Effect of an inhaled adenosine A2A agonist on the allergen induced late asthmatic response.  Eur Respir J. 2003;  22 204s
• 94 Stockley R A. The role of proteinases in the pathogenesis of chronic bronchitis.  Am J Respir Crit Care Med. 1994;  150 S109-S113
• 95 Gompertz S, Bayley D L, Hill S L. et al . Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD.  Thorax. 2001;  56 36-41
• 96 Janoff A. Elastase and emphysema. Current assessment of the protease- antiprotease hypothesis.  Am Rev Respir Dis. 1985;  132 417-433
• 97 Carp H, Miller R F, Hoidal J R. et al . Potential mechanism of emphysema: a1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity.  Proc Natl Acad Sci USA. 1982;  79 2041-2045
• 98 Yokoyama E, Nambu Z, Uchiyama I. et al . An emphysema model in rats treated intratracheally with elastase.  Environ Res. 1987;  42 340-352
• 99 Hautamaki R D, Kobayashi D K, Senior R M. et al . Requirement for Macrophage Elastase for Cigarette Smoke-Induced Emphysema in Mice.  Science. 1997;  277 2002-2004
• 100 Ohbayashi H. Neutrophil elastase inhibitors as treatment for COPD.  Exp Opin Invest Drugs. 2002;  11 1-16
• 101 Tremblay G M, Janelle M F, Bourbonnais Y. Anti-inflammatory activity of neutrophil elastase inhibitors.  Curr Opin Investig Drugs. 2003;  4 556-565
• 102 Scuri M, Botvinnikova Y, Lauredo I T. et al . Recombinant alpha-1 proteinase inhibitor blocks antigen- and mediator-induced airway responses in sheep.  J Appl Physiol. 2002;  93 1900-1906
• 103 Nagase H, Woessner J F. Matrix Metalloproteinases.  J Biol Chem. 1999;  274 21 491-21 494
• 104 Pugin J, Widmer M C, Kossodo S. et al . Human neutrophils secrete gelatinase B in vitro and in vivo in response to endotoxin and proinflammatory mediators.  Am J Respir Cell Mol Biol. 1999;  20 458-464
• 105 Ray J M, Stetler-Stevenson W G. The role of matrix metalloproteases and their inhibitors in tumor invasion, metastasis and angiogenesis.  Eur Respir J. 1994;  7 2062-2072
• 106 Busse W, Elias J, Sheppard D. et al . Airway remodeling and repair.  Am J Respir Crit Care Med. 1999;  160 1035-1042
• 107 Hoshino M, Nakamura Y, Sim J J. et al . Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation.  J Allergy Clin Immunol. 1998;  102 783-788
• 108 Cataldo D, Bettiol J, Noel A. et al . Matrix Metalloproteinase-9, but Not Tissue Inhibitor of Matrix Metalloproteinase-1, Increases in the Sputum From Allergic Asthmatic Patients After Allergen Challenge.  Chest. 2002;  122 1553-1559
• 109 Tanaka H, Miyazaki N, Oashi K S. et al . Sputum matrix metalloproteinase-9: tissue inhibitor of metalloproteinase-1 ratio in acute asthma.  J Allergy Clin Immunol. 2000;  105 900-905
• 110 Beeh K M, Beier J, Kornmann O. et al . Sputum levels of Matrixmetalloproteinase-9, Tissue Inhibitor of Metalloproteinase-1, and their ratio correlate with airway obstruction in lung transplant recipients: relation to tumor necrosis factor-alpha and interleukin 10.  J Heart Lung Transplant. 2001;  20 1144-1151
• 111 Schwingshackl A, Duszyk M, Brown N. et al . Human eosinophils release matrix metalloproteinase-9 on stimulation with TNF-alpha.  J Allergy Clin Immunol. 1999;  104 983-989
• 112 Zhang Y, McCluskey K, Fujii K. et al . Differential regulation of monocyte matrix metalloproteinase and TIMP-1 production by TNF-alpha, granulocyte-macrophage CSF, and IL-1 beta through prostaglandin-dependent and -independent mechanisms.  J Immunol. 1998;  161 3071-3076
• 113 Meisser A, Chardonnens D, Campana A. et al . Effects of tumour necrosis factor-alpha, interleukin-1 alpha, macrophage colony stimulating factor and transforming growth factor beta on trophoblastic matrix metalloproteinases.  Mol Hum Reprod. 1999;  5 252-260
• 114 Bosse M, Chakir J, Rouabhia M. et al . Serum matrix metalloproteinase-9: Tissue inhibitor of metalloproteinase-1 ratio correlates with steroid responsiveness in moderate to severe asthma.  Am J Respir Crit Care Med. 1999;  159 596-602
• 115 Quirt I, Bodurth A, Lohmann R. et al . Phase II study of marimastat (BB-2516) in malignant melanoma: a clinical and tumor biopsy study of the National Cancer Institute of Canada Clinical Trial Groups.  Invest New Drugs. 2002;  20 431-437
• 116 Reimold A M. New indications for treatment of chronic inflammation by TNF-alpha blockade.  Am J Med Sci. 2003;  325 75-92
• 117 Kuschner W G, D'Alessandro A, Wong H. et al . Dose-dependent cigarette smoking-related inflammatory response in healthy adults.  Eur Respir J. 1996;  9 1989-1994
• 118 Dubar V, Gosset P, Aerts C. et al . In vitro acute effects of tobacco smoke on tumor necrosis factor-alpha and interleukin-6 production by alveolar macrophages.  Exp Lung Res. 1993;  19 345-359
• 119 Huang S L, Su C H, Chang S C. Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis.  Am J Respir Crit Care Med. 1997;  156 1436-1439
• 120 Gan W Q, Man S F, Senthilselvan A. et al . Association between chronic obstructive pulmonary disease and systemic inflammation: a systemic review and a meta-analysis.  Thorax. 2004;  59 574-580
• 121 Brown S L, Greene M H, Gershon S K. et al . Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration.  Arthritis Rheum. 2002;  46 3151-3158
• 122 Weisman M H. What are the risks of biologic therapy in rheumatoid arthritis? An update on safety.  J Rheumatol. 2002;  65 S33-S38
• 123 Vaart H van der, Koeter G H, Postma D S. et al . First Study of Infliximab Treatment in Patients with Chronic Obstructive Pulmonary Disease.  Am J Respir Crit Care Med. 2005;  172 465-469
• 124 Trifilieff A, Walker C, Keller T. et al . Pharmacological profile of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-{alpha} converting enzyme and matrix metalloproteinases, in models of airway inflammation.  Br J Pharmacol. 2002;  135 1655-1664
• 125 Reid P. Roflumilast Altana Pharma.  Curr Opin Investig Drugs. 2002;  3 1165-1170
• 126 Sturton G, Fitzgerald M. Phosphodiesterase 4 inhibitors for the treatment of COPD.  Chest. 2002;  121 192S-196S
• 127 Karlsson J A, Souness J, Webber S. et al . Anti-inflammatory effects of the novel phosphodiesterase IV inhibitor RP 73 401.  Int Arch Allergy Immunol. 1995;  107 425-426
• 128 Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro.  J Pharmacol Exp Ther. 2001;  297 267-279
• 129 Bundschuh D S, Eltze M, Barsig J. et al . In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor.  J Pharmacol Exp Ther. 2001;  297 280-290
• 130 Profita M, Chiappara G, Mirabella F R. et al . Effect of cilomilast (Ariflo) on TNF-(alpha), IL-8, and GM-CSF release by airway cells of patients with COPD.  Thorax. 2003;  58 573-579
• 131 Timmer W, Leclerc V, Birraux G. et al . The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo.  J Clin Pharmacol. 2002;  42 297-303
• 132 Souness J E, Aldous D, Sargent C. Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors.  Immunopharmacology. 2000;  47 127-162
• 133 Schmidt B W, Kusma M, Feuring M. et al . The phosphodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis.  J Allergy Clin Immunol. 2001;  108 530-536
• 134 Bredenboeker D, Syed J, Leichtl S. et al . Roflumilast, a new orally active phosphodiesterase 4 inhibitor, is effective in the treatment of chronic obstructive pulmonary disease.  Eur Respir J. 2002;  20 374s
• 135 Crompton C H, Gubb J, Nieman R. et al . Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study.  Lancet. 2001;  358 265-270
• 136 Grootendorst D C, Gauw S A, Baan R. et al . Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease?.  Pulm Pharmacol Ther. 2003;  16 115-120
• 137 Gamble E, Grootendorst D C, Brightling C E. et al . Anti-inflammatory effects of the phosphodiesterase 4 inhibitor cilomilast (Ariflo) in COPD.  Am J Respir Crit Care Med. 2003;  168 976-982
• 138 Kuss H, Hoefgen N, Johanssen S. et al . In Vivo Efficacy in Airway Disease Models of N-(3,5-Dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic Acid Amide (AWD 12-281), a Selective Phosphodiesterase 4 Inhibitor for Inhaled Administration.  J Pharmacol Exp Ther. 2003;  307 373-385
• 139 Kudoh S. Erythromycin treatment in diffuse panbronchiolitis.  Curr Opin Pulm Med. 1998;  4 116-121
• 140 Tamaoki J. The effect of macrolides on inflammatory cells.  Chest. 2004;  125 41S-50S
• 141 Shoji T, Yoshida S, Sakamoto H. et al . Anti-inflammatory effect of roxithromycin in patients with aspitin-intolerant asthma.  Clin Exp Allergy. 1999;  29 950-956
• 142 Amayasu H, Yoshida S, Ebana S. et al . Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma.  Ann Allergy Asthma Immunol. 2000;  84 594-598
• 143 Kraft M, Cassell G H, Pak J. et al . Mycoplasma pneumoniae and Chlamydia pneumoniae in Asthma: Effect of Clarithromycin.  Chest. 2002;  121 1782-1788
• 144 Ferrara G, Losi M, Franco F. et al . Macrolides in the treatment of asthma and cystic fibrosis.  Respir Med. 2004;  99 1-10
• 145 Suzuki T, Yanai M, Yamaya M. et al . Erythromycin and Common Cold in COPD.  Chest. 2001;  120 730-733
• 146 Basyigit I, Yildiz F, Ozkara S KE. et al . The Effect of Clarithromycin on Inflammatory Markers in Chronic Obstructive Pulmonary Disease: Preliminary Data.  Ann Pharmacother. 2004;  38 1400-1405
• 147 Banerjee B, Honeybourne D, Khair O A. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial.  Treat Respir Med. 2004;  3 59-65
• 148 Borok Z, Buhl R, Grimes G J. et al . Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis.  Lancet. 1991;  338 215-216
• 149 Beeh K M, Beier J, Haas I C. et al . Glutathione deficiency of the lower respiratory tract in patients with idiopathic pulmonary fibrosis.  Eur Respir J. 2002;  19 1119-1123
• 150 Behr J, Maier K, Degenkolb B. et al . Antioxidative and clinical Effects of high-dose N-Acetylcysteine in fibrosing alveolitis.  Am J Respir Crit Care Med. 1997;  156 1897-1901
• 151 Cantin A M, Hubbard R C, Crystal R G. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis.  Am Rev Respir Dis. 1989;  139 370-372
• 152 Bowler R P, Crapo J D. Oxidative stress in allergic respiratory diseases.  J Allergy Clin Immunol. 2002;  110 349-356
• 153 Behr J, Maier K, Braun B. et al . Evidence for oxidative stress in bronchiolitis obliterans syndrome after lung and heart-lung transplantation. The Munich Lung Transplant Group.  Transplantation. 2000;  69 1856-1860
• 154 Riise G C, Williams A, Kjellstrom C. et al . Bronchiolitis obliterans syndrome in lung transplant recipients is associated with increased neutrophil activity and decreased antioxidant status in the lung.  Eur Respir J. 1998;  12 82-88
• 155 MacNee W. Oxidants/antioxidants and chronic obstructive pulmonary disease: pathogenesis to therapy.  Novartis Found Symp. 2001;  234 169-185
• 156 Pela R, Calcagni A M, Subiaco S. et al . N-Acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPD.  Respiration. 1999;  66 495-500
• 157 Stey C, Steurer J, Bachmann S. et al . The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review.  Eur Respir J. 2000;  16 253-262
• 158 Grandjean E M, Berthet P, Ruffmann R. et al . Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials.  Clin Ther. 2000;  22 209-221
• 159 Benedetto F de, Aceto A, Dragani B. et al . Long-term oral n-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD.  Pulm Pharmacol Ther. 2005;  18 41-47
• 160 Kasielski M, Nowak D. Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease.  Respir Med. 2001;  95 448-456
• 161 Decramer M, Rutten-van Mölken M, Dekhuijzen P N. et al . Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial.  Lancet. 2005;  365 1552-1560
• 162 Malerba M, Ponticello A, Radaeli A. et al . Effect of twelve-months therapy with oral ambroxol in preventing exacerbations in patients with COPD. Double-blind, randomized, multicenter, placebo-controlled study (the AMETHIST Trial).  Pulm Pharmacol Ther. 2004;  17 27-34
• 163 Antonicelli F, Brown D, Parmentier M. et al . Regulation of LPS-mediated inflammation in vivo and in vitro by the thiol antioxidant Nacystelyn.  Am J Physiol Lung Cell Mol Physiol. 2004;  286 L1319-L1327
• 164 Nagy A M, Vanderbist F, Parij N. et al . Effect of the mucoactive drug nacystelyn on the respiratory burst of human blood polymorphonuclear neutrophils.  Pulm Pharmacol Ther. 1997;  10 287-292
• 165 App E M, Baran D, Dab I. et al . Dose-finding and 24-h monitoring for efficacy and safety of aerosolized Nacystelyn in cystic fibrosis.  Eur Respir J. 2002;  19 294-302
• 166 Leckie M J, ten Brinke A, Khan J. et al . Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response.  Lancet. 2000;  356 2144-2148
• 167 Gabrijelcic J, Acuna A, Profita M. et al . Neutrophil airway influx by platelet-activating factor in asthma: role of adhesion molecules and LTB4 expression.  Eur Respir J. 2003;  22 290-297
• 168 Nightingale J A, Rogers D F, Hart L A. et al . Effect of inhaled endotoxin on induced sputum in normal, atopic, and atopic asthma subjects.  Thorax. 1998;  53 563-571
• 169 Brightling C E, Monterio W, Green R H. et al . Induced sputum and other outcome measures in chronic obstructive pulmonary disease: safety and repeatability.  Respir Med. 2001;  95 1999-2002
• 170 Senn S. Sample size issues. In: Senn S (ed.). Crossover trials in clinical research, 2. ed. Chichester: Wiley & Sons Ltd 2002: 277-286
• 171 Belda J, Leigh R, Parameswaran K. et al . Induced sputum cell counts in healthy adults.  Am J Respir Crit Care Med. 2000;  161 475-478
• 172 Pizzichini M MM, Popov T A, Efthimiadis A. et al . Spontaneous and induced sputum to measure indices of airway inflammation in asthma.  Am J Respir Crit Care Med. 1996;  154 866-869
• 173 Beier J, Beeh K M, Semmler D. et al . Increased concentrations of glutathione in induced sputum in patients with mild or moderate allergic asthma.  Ann Allergy Asthma Immunol. 2004;  92 459-463
• 174 Stanescu D, Sanna A, Veriter C. et al . Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils.  Thorax. 1996;  51 267-271
• 175 Culpitt S V, Matos C de, Russell R E. et al . Effects 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
• 176 Loppow D, Schleiss M B. et al . In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation.  Respir Med. 2001;  95 115-121
• 177 Silkoff P E, Martin D, Pak J. et al . Exhaled nitric oxide correlated with induced sputum findings in COPD.  Chest. 2001;  119 1049-1055
• 178 Paredi P, Kharitonov S A, Loukides S. et al . Exhaled nitric oxide is increased in active fibrosing alveolitis.  Chest. 1999;  115 1352-1356
• 179 Gessner C, Hammerschmidt S, Kuhn H. et al . Gehauchte Diagnosen? Zum Potenzial von Atemkondensatuntersuchungen.  Pneumologie. 2004;  58 230-237
• 180 Kharitonov S A. Exhaled markers of inflammatory lung diseases: ready for routine monitoring?.  Schweiz Med Wschr. 2003;  134 175-192
• 181 Godaly G, Hang L, Frendeus B. et al . Transepithelial Neutrophil Migration Is CXCR1 Dependent In Vitro and Is Defective in IL-8 Receptor Knockout Mice.  J Immunol. 2000;  165 5287-5294
• 182 Beeh K M, Beier J, Ernst M. et al . Platinum-based, leukocyte-depleting chemotherapy does not alter induced sputum markers of neutrophilic inflammation in COPD-patients with unresectable non-small-cell lung cancer.  Respiration. 2003;  70 166-171