COPD Update 2015: Zellbiologie goes Clinic? – Wichtige Forschungsergebnisse für den Kliniker

 

 Permissions and Reprints

Zusammenfassung

Die COPD ist eine sehr häufige, chronische, nicht ansteckende Erkrankung, die weltweit eine hohe Mortalität und hohe sozioökonomische Kosten verursacht. Ihre klinische Betrachtung wird zunehmend umfassender und beinhaltet unter anderem die Lungenfunktion, die Exazerbationshäufigkeit, die körperliche Leistungsfähigkeit, das Dyspnoeempfinden und Komorbiditäten. Auf der anderen Seite sind unsere therapeutischen Möglichkeiten aber sehr eingeschränkt: Es gibt zwar mehrere gut verträgliche und wirksame, kombinierbare Bronchodilatatoren aus der Gruppe der langwirksamen Beta2-Mimetika und Anticholinergika, aber kaum Medikamente, die ursächlich in der Pathophysiologie angreifen. Als antiinflammatorische Prinzipien stehen nur die inhalierbaren Glukokortikoide und ein oral verfügbarer Inhibitor der Phosphodiesterase 4 zur Verfügung, die jeweils bei einem Teil der Patienten zu einer Verbesserung der Lungenfunktion führen können. Dieser Mangel an wirksamen ursächlichen Therapieprinzipien einerseits und an Biomarkern für eine klare Patientenstratifizierung andererseits liegt zu großen Teilen in unserem limitierten Verständnis der Pathophysiologie begründet. Daher sollen im Folgenden die aktuellen Fortschritte der klinischen und experimentellen Forschung zur COPD mit Bezug zur Praxis zusammenhängend dargestellt werden.

Abstract

The COPD is a very common, chronic, non-contagious disease causing high mortality as well as high socio-economical costs worldwide. Its clinical assessment progressively becomes more comprehensive including the lung function, the rate of exacerbations, the physical capacity, the sensation of dyspnoea, and comorbidities. On the other hand, our therapeutic options are very limited: Although there are several well-tolerated and effective combinable bronchodilators of the group of long-acting beta2-mimetics and anticholinergics, drugs causally affecting pathophysiology are barely available. As anti-inflammatory principles only inhaled glucocorticoids as well as one orally available inhibitor of phosphodiesterase 4 are approved, each improving the course of disease in a subgroup of patients. This lack of effective causative therapeutic principles on the one hand and of biomarkers clearly stratifying patients on the other hand to a large extend are caused by our limited understanding of the pathophysiology. Therefore, this review presents the current progress in clinical and experimental research on COPD with regard to clinical practice.

• Literatur

• 1 Gibson J, Loddenkemper R, Sibille Y et al, Hrsg. The European Lung White Book: Respiratory Health and Disease in Europe. 2nd. revised edition. European Respiratory Society; 2013
  Google Scholar
• 2 Vestbo J, Agusti A, Wouters EF et al. Should we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team. Am J Respir Crit Care Med 2014; 189: 1022-1030
  CrossrefPubMedGoogle Scholar
• 3 Gillissen A. [Novel drugs for COPD treatment]. Pneumologie 2014; 68: 594-598
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Mushtaq Y. The COPD pipeline. Nature reviews Drug discovery 2014; 13: 253
  CrossrefPubMedGoogle Scholar
• 5 Dijkstra AE, Postma DS, van Ginneken B et al. Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses. Am J Respir Crit Care Med 2015; 191: 547-556
  CrossrefPubMedGoogle Scholar
• 6 Castaldi PJ, Cho MH, San Jose Estepar R et al. Genome-wide association identifies regulatory Loci associated with distinct local histogram emphysema patterns. Am J Respir Crit Care Med 2014; 190: 399-409
  CrossrefPubMedGoogle Scholar
• 7 Stanley SE, Chen JJ, Podlevsky JD et al. Telomerase mutations in smokers with severe emphysema. J Clin Invest 2015; 125: 563-570
  CrossrefPubMedGoogle Scholar
• 8 Bowler RP, Jacobson S, Cruickshank C et al. Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes. Am J Respir Crit Care Med 2015; 191: 275-284
  CrossrefPubMedGoogle Scholar
• 9 Ahmed FS, Jiang XC, Schwartz JE et al. Plasma sphingomyelin and longitudinal change in percent emphysema on CT. The MESA lung study. Biomarkers 2014; 19: 207-213
  CrossrefPubMedGoogle Scholar
• 10 Telenga ED, Hoffmann RF, tʼKindt R et al. Untargeted lipidomic analysis in chronic obstructive pulmonary disease. Uncovering sphingolipids. Am J Respir Crit Care Med 2014; 190: 155-164
  CrossrefPubMedGoogle Scholar
• 11 Innes AL, Woodruff PG, Ferrando RE et al. Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest 2006; 130: 1102-1108
  CrossrefPubMedGoogle Scholar
• 12 Roy MG, Livraghi-Butrico A, Fletcher AA et al. Muc5b is required for airway defence. Nature 2014; 505: 412-416
  PubMedGoogle Scholar
• 13 Xue J, Schmidt SV, Sander J et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 2014; 40: 274-288
  CrossrefPubMedGoogle Scholar
• 14 Mizumura K, Cloonan SM, Nakahira K et al. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J Clin Invest 2014; 124: 3987-4003
  CrossrefPubMedGoogle Scholar
• 15 Heijink IH, Noordhoek JA, Timens W et al. Abnormalities in airway epithelial junction formation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014; 189: 1439-1442
  CrossrefPubMedGoogle Scholar
• 16 Staudt MR, Buro-Auriemma LJ, Walters MS et al. Airway Basal stem/progenitor cells have diminished capacity to regenerate airway epithelium in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014; 190: 955-958
  CrossrefPubMedGoogle Scholar
• 17 Inoue H, Nagata N, Kurokawa H et al. iPS cells: a game changer for future medicine. The EMBO journal 2014; 33: 409-417
  CrossrefPubMedGoogle Scholar
• 18 Zuo W, Zhang T, Wu DZ et al. p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration. Nature 2015; 517: 616-620
  PubMedGoogle Scholar
• 19 Ott HC, Clippinger B, Conrad C et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nature Med 2010; 16: 927-933
  CrossrefPubMedGoogle Scholar
• 20 Petersen TH, Calle EA, Zhao L et al. Tissue-engineered lungs for in vivo implantation. Science 2010; 329: 538-541
  CrossrefPubMedGoogle Scholar
• 21 Drummond MB, Kirk GD. HIV-associated obstructive lung diseases: insights and implications for the clinician. Lancet Respir Med 2014; 2: 583-592
  CrossrefPubMedGoogle Scholar
• 22 Popescu I, Drummond MB, Gama L et al. Activation-induced cell death drives profound lung CD4(+) T-cell depletion in HIV-associated chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014; 190: 744-755
  CrossrefPubMedGoogle Scholar
• 23 Celli BR, Locantore N, Yates J et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185: 1065-1072
  CrossrefPubMedGoogle Scholar
• 24 Stolz D, Meyer A, Rakic J et al. Mortality risk prediction in COPD by a prognostic biomarker panel. Eur Respir J 2014; 44: 1557-1570
  CrossrefPubMedGoogle Scholar
• 25 Coxson HO, Dirksen A, Edwards LD et al. The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the ECLIPSE study. Lancet Respir Med 2013; 1: 129-136
  CrossrefPubMedGoogle Scholar
• 26 Galban CJ, Han MK, Boes JL et al. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nature Med 2012; 18: 1711-1715
  CrossrefPubMedGoogle Scholar
• 27 Mallia P, Message SD, Contoli M et al. Neutrophil adhesion molecules in experimental rhinovirus infection in COPD. Resp Res 2013; 14: 72
  CrossrefPubMedGoogle Scholar
• 28 Mallia P, Message SD, Contoli M et al. Lymphocyte subsets in experimental rhinovirus infection in chronic obstructive pulmonary disease. Resp Med 2014; 108: 78-85
  CrossrefPubMedGoogle Scholar
• 29 Molyneaux PL, Mallia P, Cox MJ et al. Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 188: 1224-1231
  CrossrefPubMedGoogle Scholar
• 30 Gohy ST, Detry BR, Lecocq M et al. Polymeric immunoglobulin receptor down-regulation in chronic obstructive pulmonary disease. Persistence in the cultured epithelium and role of transforming growth factor-beta. Am J Respir Crit Care Med 2014; 190: 509-521
  CrossrefPubMedGoogle Scholar
• 31 Kalathil SG, Lugade AA, Pradhan V et al. T-regulatory cells and programmed death 1+ T cells contribute to effector T-cell dysfunction in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014; 190: 40-50
  CrossrefPubMedGoogle Scholar
• 32 Kiser TH, Allen RR, Valuck RJ et al. Outcomes associated with corticosteroid dosage in critically ill patients with acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014; 189: 1052-1064
  CrossrefPubMedGoogle Scholar
• 33 Celli BR, Decramer M, Wedzicha JA et al. An official American Thoracic Society/European Respiratory Society statement: research questions in COPD. Eur Respir J 2015; 45: 879-905
  CrossrefPubMedGoogle Scholar
• 34 Magnussen H, Disse B, Rodriguez-Roisin R et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014; 371: 1285-1294
  CrossrefPubMedGoogle Scholar
• 35 Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet 2009; 373: 1905-1917
  CrossrefPubMedGoogle Scholar
• 36 Bafadhel M, Davies L, Calverley PM et al. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J 2014; 44: 789-791
  CrossrefPubMedGoogle Scholar
• 37 Christenson SA, Steiling K, van den Berge M et al. Asthma-COPD Overlap. Clinical Relevance of Genomic Signatures of Type 2 Inflammation in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015; 191: 758-766
  CrossrefPubMedGoogle Scholar
• 38 Babu KS, Morjaria JB. Emerging therapeutic strategies in COPD. Drug Discov Today 2015; 20: 371-379
  CrossrefPubMedGoogle Scholar
• 39 Neukamm A, Hoiseth AD, Einvik G et al. Rosuvastatin treatment in stable chronic obstructive pulmonary disease (RODEO): a randomized controlled trial. J Intern Med 2015; 278: 59-67
  CrossrefPubMedGoogle Scholar
• 40 Criner GJ, Connett JE, Aaron SD et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med 2014; 370: 2201-2210
  CrossrefPubMedGoogle Scholar
• 41 Ingebrigtsen TS, Marott JL, Nordestgaard BG et al. Statin use and exacerbations in individuals with chronic obstructive pulmonary disease. Thorax 2015; 70: 33-40
  CrossrefPubMedGoogle Scholar
• 42 Martinez FJ, Calverley PM, Goehring UM et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015; 385: 857-866
  CrossrefPubMedGoogle Scholar
• 43 Bardin PG, Dorward MA, Lampe FC et al. Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen. Br J Clin Pharmacol 1998; 45: 387-391
  CrossrefPubMedGoogle Scholar
• 44 Franciosi LG, Diamant Z, Banner KH et al. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med 2013; 1: 714-727
  CrossrefPubMedGoogle Scholar
• 45 Gaffey K, Reynolds S, Plumb J et al. Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs. Eur Respir J 2013; 42: 28-41
  CrossrefPubMedGoogle Scholar
• 46 Schmeck B, Zahlten J, Moog K et al. Streptococcus pneumoniae-induced p38 MAPK-dependent phosphorylation of RelA at the interleukin-8 promotor. J Biol Chem 2004; 279: 53241-53247
  CrossrefPubMedGoogle Scholar
• 47 MacNee W, Allan RJ, Jones I et al. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax 2013; 68: 738-745
  CrossrefPubMedGoogle Scholar
• 48 Calverley PM. New treatments for COPD: many miles still to go. Lancet Respir Med 2014; 2: 6-7
  CrossrefPubMedGoogle Scholar
• 49 Russell P, Cass L, Ito K et al. Safety, pharmacokinetic and pharmacodynamic profile of RV568, a narrow spectrum kinase inhibitor, following repeat inhaled dosing in COPD patients European Respiratory Society. Annual Congress; 2013
  PubMedGoogle Scholar
• 50 Hsu AC, Starkey MR, Hanish I et al. Targeting PI3K-p110alpha Suppresses Influenza Viral Infection in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015; 191: 1012-1023
  CrossrefPubMedGoogle Scholar
• 51 Wells JM, O'Reilly PJ, Szul T et al. An aberrant leukotriene A4 hydrolase-proline-glycine-proline pathway in the pathogenesis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014; 190: 51-61
  CrossrefPubMedGoogle Scholar
• 52 Paige M, Wang K, Burdick M et al. Role of leukotriene A4 hydrolase aminopeptidase in the pathogenesis of emphysema. J Immunol 2014; 192: 5059-5068
  CrossrefPubMedGoogle Scholar
• 53 Zheng JP, Wen FQ, Bai CX et al. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med 2014; 2: 187-194
  CrossrefPubMedGoogle Scholar
• 54 Albert RK, Connett J, Bailey WC et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011; 365: 689-698
  CrossrefPubMedGoogle Scholar
• 55 WHO. Chronic obstructive pulmonary disease (COPD). World Health Organization fact sheet 315. Im Internet: http://www.who.int/mediacentre/factsheets/fs315/en [Stand: 30.10.2014]
  Google Scholar
• 56 Brightling CE, Bleecker ER, Panettieri Jr RA et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med 2014; 2: 891-901
  CrossrefPubMedGoogle Scholar
• 57 Castro M, Wenzel SE, Bleecker ER et al. Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2014; 2: 879-890
  CrossrefPubMedGoogle Scholar
• 58 Rennard SI, Dale DC, Donohue JF et al. CXCR2 Antagonist MK-7123-A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015; 191: 1001-1011
  CrossrefPubMedGoogle Scholar
• 59 Kearley J, Silver JS, Sanden C et al. Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. Immunity 2015; 42: 566-579
  CrossrefPubMedGoogle Scholar
• 60 Jackson DJ, Makrinioti H, Rana BM et al. IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo. Am J Respir Crit Care Med 2014; 190: 1373-1382
  CrossrefPubMedGoogle Scholar
• 61 Byers DE, Alexander-Brett J, Patel AC et al. Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J Clin Invest 2013; 123: 3967-3982
  CrossrefPubMedGoogle Scholar
• 62 Sims MW, Margolis DJ, Localio AR et al. Impact of pulmonary artery pressure on exercise function in severe COPD. Chest 2009; 136: 412-419
  CrossrefPubMedGoogle Scholar
• 63 Dournes G, Laurent F, Coste F et al. Computed tomographic measurement of airway remodeling and emphysema in advanced chronic obstructive pulmonary disease. Correlation with pulmonary hypertension. Am J Respir Crit Care Med 2015; 191: 63-70
  CrossrefPubMedGoogle Scholar
• 64 Blanco I, Gimeno E, Munoz PA et al. Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Am J Respir Crit Care Med 2010; 181: 270-278
  CrossrefPubMedGoogle Scholar
• 65 Goudie AR, Lipworth BJ, Hopkinson PJ et al. Tadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med 2014; 2: 293-300
  CrossrefPubMedGoogle Scholar
• 66 Brusselle G. Should we pursue pulmonary vasodilation in patients with COPD?. Lancet Respir Med 2014; 2: 252-254
  CrossrefPubMedGoogle Scholar
• 67 Bond RA. The intrinsic bias of generalizations. Am J Respir Crit Care Med 2014; 189: 359
  CrossrefPubMedGoogle Scholar
• 68 Vonk-Noordegraaf A, Boerrigter BG. Sildenafil: a definitive NO in COPD. Eur Respir J 2013; 42: 893-894
  CrossrefPubMedGoogle Scholar
• 69 Seimetz M, Parajuli N, Pichl A et al. Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell 2011; 147: 293-305
  CrossrefPubMedGoogle Scholar