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  • 1. Is COPD An Inflammatory Disease? Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university Presentation1.lnk
  • 2. Global Strategy for Diagnosis, Management and Prevention of COPD Definition of COPD ◙ COPD, a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. ◙ Exacerbations and comorbidities contribute to the overall severity in individual patients.
  • 3. The Real Story
  • 4. 66 Angiogenesis in COPD Reprinted from International Journal of COPD, 2, Siafakas NM, et al., Role of angiogenesis and vascular remodeling in chronic obstructive pulmonary disease, 453-462, Copyright 2007, with permission from Dove Medical Press Ltd. extravasated plasma proteins Inflammatory cells (Mac, Neu, Epith, Lymph) Release of angiogenic mediators Fibrinogen products Inflammation Tissue hypoxia Airway fibrosis Mechanical Injury Increased blood flow Vessel growth Angiogenesis Vascular remodeling Up-regulation of Angiogenic factors Shear stress on the endothelium
  • 5. 77 Angiogenic and Angiostatic Factors in COPD  Angiogenic CXC Chemokines, CC Chemokines, and Growth Factors: – CXCL1 – CXCL5 – CXCL8 – CCL2 – VEGF – bFGF – Angiopoietin-1 – HGF – EGF  Angiostatic CXC Chemokines, CC Chemokines, and Growth Factors: – CXCL10 – CXCL11 Siafakas NM, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:453-462.
  • 6. 88 VEGF in COPD Santos S, et al. Am J Respir Crit Care Med. 2003;167:1250-1256. Reproduced with permission from American Thoracic Society. Copyright © 2003 Moderate COPDNonsmoker Severe emphysema a = Pulmonary muscularartery br = Bronchiole
  • 7. 99 VEGF Levels in Stable COPD Adapted from Kanazawa H. Med Sci Monit. 2007;13:RA189-195. ** P<0.05 vs.controls 7000 6000 5000 4000 3000 2000 1000 0 VEGFlevels(pg/ml) Normal controls Bronchitis type Emphysema type COPD patients ** **
  • 8. 1010 Serum VEGF Is Elevated in COPD Exacerbations Adapted from Valipour A, et al. Clin Sci (Lond). 2008;115:225-232. 1,500 1,000 500 0 VERGFser(pg/ml) Exacerbation Recovery P=0.032
  • 9. 1111 SIgA Deficiency Is Associated With Airway Remodeling Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Polosukhin VV,et al. Am J Respir Crit Care Med. 2011;184:317-327. Official journal of the American Thoracic Society. SIgA = secretoryimmunoglobulin A
  • 10. 1212 Remodeling Is Increased in IgA Deficient Airways and lower SIgA Is Correlated With Lower FEV1 * P<0.01 compared with lifelong nonsmokers (never smokers). ** P<0.01 compared with surface SIgA- positive airways from the same clinical group. Never Smokers Former Smokers COPD I-II COPD III-IV 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 VMsub(mm) IgA-positive airways IgA-deficientairways Average ** ** ** ** * ** *** * * * 0.025 0 20 40 60 80 100 120 IntensityofIgA-specific FluorescentSignal(apv) Never smokers Former smokers COPD I-II COPD I-II r = -0.847 p< 0.001 0.050 0.075 0.100 0.125 0.150 0.175 VVsub (mm) 0 0 20 40 60 80 100 SlgAConcentration (g/ml) 20 40 60 80 100 120 FEV1 140 r = 0.516 p< 0.05 Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Polosukhin VV,et al. Am J Respir Crit Care Med. 2011;184:317-327. Official journal of the American Thoracic Society.
  • 11. 1313 COPD Is a Disease Characterised by Inflammation Reproduced from The Lancet, Vol 364, Barnes PJ & Hansel TT, "Prospects for new drugs for chronic obstructive pulmonary disease", pp985-96. Copyright © 2004, with permission from Elsevier. Cigarette smoke Epithelial cells CD8+ Tc cell Emphysema Proteases Mucous hypersecretion Macrophage/Dendritic cell Neutrophil Monocyte Fibroblast Obstructive bronchiolitis Fibrosis
  • 12. 14 COPDforum is supported by Inflammatory Cells in Stable COPD
  • 13. 1515 Neutrophils in COPD Mucoushypersecretion Serine proteases Neutrophil Elastase Cathepsin G Proteinase-3  O2 - MPO LTB4,IL-8, GRO- LTB4,IL-8 Adapted from Barnes PJ. N Engl J Med. 2000; 343: 269-280 Adapted from Barnes PJ, et al. Eur Respir J. 2003; 22: 672-688 Emphysema Severe emphysema Images courtesy R Buhl.
  • 14. 1616 Sputum Neutrophil Count Correlates With Declining Lung Function Reproduced with permission of Thorax from “Airways obstruction, chronic expectoration and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils,” Stanescu et al, Vol 51, Copyright © 1996; permission conveyed through Copyright Clearance Center, Inc. > 30 < 20 100 0 NeutrophilsiniInducedsputum(%) 90 20 – 30 80 60 70 50 40 FEV1 decline (mL/year) P<0.01
  • 15. 1717 Neutrophils Infiltrating Bronchial Glands in COPD Saetta M, et al. Am J Respir Crit Care Med. 1997;156:1633-1639. Reproduced with permission from American Thoracic Society. Copyright © 1997
  • 16. 1818 Reduction in Neutrophil Apoptosis in COPD Adapted from Brown V, et al. Respir Res. 2009;10:24. Apoptotic neutrophils (arrows) *P<0.05 *P<0.01 MorphologyTunel NS HS COPD 60 50 40 30 20 10 0 Apoptotic neutrophils [%] Image courtesyof R Buhl. NS: nonsmoking controls (n=9) HS: healthy smoking controls (n=9) TUNEL: the terminal transferase- mediated dUTP nick end-labeling method
  • 17. 1919 Alveolar Macrophages in COPD  Phagocytosis Cigarette smoke Wood smoke Elastolysis MMP-9,MMP-12 Cathepsins K, L, S Emphysema Steroid resistance NO ROSONOO-  HDAC  Steroid response Monocytes MCP-1 GRO- Neutrophils LTB4 IL-8 GRO- CD8+ Cells IP-10 Mig I-TAC Adapted from Barnes PJ. J COPD. 2004;1:59-70. Copyright © 2004 from "Alveolar Macrophages as Orchestrators of COPD" by Barnes. Reproduced by permission of Taylor & Francis Group, LLC., www.taylorandfrancis.com Emphysema Severe emphysema Images courtesy of R Buhl.  Numbers  Secretion
  • 18. 20 COPDforum is supported by Inflammatory Mediators in Stable COPD
  • 19. 2121 CD8+ Cells in COPD Adapted from Berke G. Ann Rev Immunol. 1994; 12: 735-773. Cosio MG, et al. Chest. 2002;121:160S-165S Adapted from Grumelli S, et al PLoS Med. 2004;1: 75-83. Majo J, et al. Eur Respir J. 2001;17:946-953 Cytotoxic T-Cell (CD8+: Tc1 Cell) Macrophage Bronchiolar epithelial cells IP-10, Mig, I-TAC CXCR3 Perforins Granzyme B Emphysema (Apoptosis of Type I pneumocytes) IFN-
  • 20. 2222 The Greater the CD8+ Infiltration, the Greater the Airway Obstruction Saetta M, et al. Am J Respir Crit Care Med. 1998;157:822-826. Reproduced with permission from American Thoracic Society. Copyright © 1998. 1000 P=0.01 rho= –0.63 N=6 0 200 400 600 0 50 60 70 80 90 110 FEV1 (% predicted) CD8+(cells/mm2) 100 800
  • 21. 2323 Increased CD8+ Cell Numbers in the Submucosa of Large and Small Airways, Vessels and Alveolar Wall of Smokers Who Develop COPD Saetta M, et al. Am J Respir Crit Care Med. 1999;160:711-717. Reproduced with permission from American Thoracic Society. Copyright © 1999 L I E Jeffery PK. Chest. 2000; 117: 251S-260S.Courtesy of Dr Marina Saetta BronchioleAlveoli BronchusPulmonaryartery
  • 22. 2424 Siena L, et al. Respir Med. 2011;105:1491-500. Apoptosis of CD8+ Cell Is Decreased in Mild-to-Moderate COPD and Is Associated With Lower FEV1  Background – CD8+ T-lymphocytes are crucial effector and regulatory cells in inflammation and are increased in the central and peripheral airways in COPD.  Study Information: – This study assessed the role of apoptosis in the accumulation of CD8+ T- lymphocytes within the airway wall in COPD. – TUNEL and immunohistochemistry techniques were used to identify apoptosis and cell phenotype, respectively.  Key Results: – The percentage of apoptotic CD8+ T-lymphocytes was significantly lower (P <0.0001) in smokers with mild-to-moderate COPD than in non-smokers, smokers with normal lung function, and smokers with severe/very severe COPD. – Level of apoptotic CD8+ cells in central and peripheral airways were positively related to values of FEV1 and FEV1/FVC ratio. These data suggest that reduced apoptosis of CD8+ T-lymphocytes may be an important mechanism that contributes to the accumulation of these cells in the airway submucosa in smokers with mild/moderate COPD.
  • 23. 2525 Emphysema Is Associated With Inflammatory Cells in the Alveoli Cells/mm-1 Nonsmokers N=6 Smokers without emphysema N=5 Smokers with emphysema N=10 Elastase+ 2.24 1.61 1.40 CD3+ 0.95 0.75 1.81 CD4+ 0.41 0.25 0.71 CD8+ 0.20 0.26 0.63 Adapted from Majo J, et al. Eur Respir J. 2001;17:946-953.
  • 24. 2626 Numbers of Inflammatory Cells and Mediators Increase as Disease Progresses Percent of Airways with Measurable Cells (%) by GOLD Stage Cell Type I II III IV PMNs 67 55 84 100 Macrophages 54 66 73 92 Eosinophils 25 33 29 32 CD4+ 63 87 77 94 CD8+ 85 80 88 98 B cells 7 8 45 37 Adapted from Hogg JC, et al. N Engl J Med. 2004;350:2645-2653. PMN = Polymorphonuclear cells
  • 25. 2727 Inflammatory Mediators in COPD – Summary Cell Neutrophils Macrophages T-cell Epithelialcell IL-8, TGF- 1, IP-10, Mig, I-TAC, LTB4, GRO- , MCP-1, MMP-9 Granzyme B, perforins, IFN-, TNF- IL-8, IL-6, TGF-1 TGF-, IP-10, Mig, I-TAC, LTB4, GRO-, MCP-1, ROS, MMP-9 Serine proteases, TNF-, ROS, IL-8, MPO, LTB4 Selected Mediators Barnes PJ, et al. Eur Respir J. 2003;22:672-888.
  • 26. 2828 Examples of Chemotactic Factors in COPD Barnes PJ. Curr Opin Pharmacol. 2004;4:263-272. Hill AT, et al. Am J Respir Crit Care Med. 1999;160: 893-898. Montuschi P, et al. Thorax. 2003;58:585-588.  MCP-1  GRO-  Elastin fragments  LTB4  IL-8  GRO-  Elastin fragments  IP-10  Mig  I-TAC Neutrophil Monocyte T-cell
  • 27. 2929 TNF- Has Pro-inflammatory Actions in COPD Mukhopadhyay S, et al. Respir Res. 2006;7:125. Reproduced with permission from Biomed Central. Oxidative stress Activation of NF-B and AP-1 Activation of proinflammatorymolecules e.g.VCAM-1,ICAM-1 and RAGE SubcellularROS production TNF- Antioxidants e.g. GSH, Catalase Scavenge free radicals, detoxifycellular hydrogen peroxideand inhibit ROS generation Proinflammation + + + + + + + - -
  • 28. 3030 Levels of TNF-α in Exhaled Breath Condensate in Stable COPD and Exacerbations Reprinted from International Journal of COPD, 4, Ko FW, et al., Measurement of tumor necrosis factor-alpha, leukotriene B4, and interleukin 8 in the exhaled breath condensate in patients with acute exacerbations of chronic obstructive pulmonary disease,79-86, Copyright 2009, with permissions from Dove Medical Press Ltd. Int J Chron Obstruct Pulmon Dis. 2009;4:79-86. Exacerbation 25 20 15 10 5 0 LevelofTNFαinexhaledBreath condensate(pg/ml) Day 5 Day 14 Day 30 Day 60 Stable COPD Normal P=0.017 P=0.036 P=0.045 P=0.009
  • 29. 3131 COPD Inflammatory Mediators: TGF-1  TGF-1 is elevated in airways of patients with COPD1  TGF-1 expression is partly responsible for small airway fibrosis1,2  TGF-1 mRNA correlates positively with pack-years of tobacco abuse and degree of small airway obstruction3  Several studies to show that TGF- 1 reduces -agonist receptors and function3 1. de Boer WI, et al. Am J Respir Crit Care Med. 1998;158:1951-1957. 2. Vignola AM, et al. Am J Respir Crit Care Med. 1997;156:591-599. 3. Takizawa H, et al. Am J Respir Crit Care Med. 2001;163:1476-1483.
  • 30. 3232 Increased TGF-1 in COPD Small Airway Epithelium de Boer WI, 1998, “Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, Vol 158:1951-1957. Official Journal of the American Thoracic Society © American Thoracic Society, Christina Shepherd, Managing Editor, 9/18/08. Bronchiole Macrophage Fibrosis
  • 31. 3333 IL-6 Concentrations in Exhaled Breath Condensates Reproduced from Respiratory Medicine, Vol 97, Bucchioni et al. "High levels of interleukin-6 in the exhaled breath condensate of patients with COPD," pp1299-1302, Copyright © 2003, with permission from Elsevier. Control COPD 10.0 7.5 5.0 2.5 IL-6(pg/mL) 0.0 P<0.0001
  • 32. 3434 Increased Bronchiolar Expression of the T-Cell Chemokine Receptor CXCR3 Saetta M, et al. Am J Respir Crit Care Med. 2002;165:1404-1409. Reproduced with permission from American Thoracic Society. Copyright © 2002 COPD (Smoker) Smoker (Normal lung function) Non-smoker (Normal lung function) Arrows indicate CXCR3+ cells.Nucleicounterstainedwith nuclearfastred (x40) be = Bronchiolar epithelium; bs = Bronchiolar submucosa
  • 33. 3535 Elastins in the Development of Emphysema Reproduced with permission of Nature Med, from “Antielastin autoimmunity in tobacco smoking-induced emphysema,” Lee et al, Vol 13, Copyright © 2007; permission conveyed through Copyright Clearance Center, Inc. ROS Antigen-presenting cell B cell Macrophage Elastase Cigarette smoke Neutrophil elastase Macrophage MMP12 MMP9 Cigarette smoke Innate immunity Adaptive immunity CD25 TRC Tr CXCR3 Neutrophil TCR/MHC-11 Elastin peptides IFN- 1AT MMP12 MMP9 CXCL10 CXCR3 TH1 cell CXCL9 Emphysema Normal lung
  • 34. 3636 Actions of Proteinases in COPD Reprinted from International Journal of COPD, 3, Owen CA, Roles for proteinases in the pathogenesis of chronic obstructive pulmonary disease, 253-268, Copyright 2008, with permission from Dove Medical Press Ltd. MMP Inflammation MMP SP ADAMs MMP SP ADAMs T Cells Structural Cells CP CP GRZ MMP SP CP SP ADAMs Proteinases Growth factor activation Small Airway Fibrosis Septal Cell Apoptosis ECM Degradation Airspace Enlargement Mucous Secretion Bacterial Infection Elastin Fragments Cytokine Production or Activation Defective Repair IP-10 MAC PMN COPD
  • 35. 3737 Elevation of Matrix Metalloproteinase in COPD Counts of MMP-2-Positive Macrophages 100 80 60 40 20 0 Severe COPD (GOLD III–IV) Mild/moderate COPD (GOLD I–II) Control smokers Non- smokers MMP-2+ macrophages(%) P=0.002 P=0.003 P=0.001 P=0.01 P=0.0001 Reproduced with permission of Chest, from “Matrix metalloproteinase-2 Protein in Lung Periphery is Related to COPD Progression,” Baraldo et al, Vol 132, Copyright © 2007; permission conveyed through Copyright Clearance Center, Inc.
  • 36. 3838 MMP-9 Is Elevated in Patients With COPD Adapted from Beeh et a l. Respir Med. 2003;97:634-639. 914 44 0 100 200 300 400 500 600 700 800 900 1000 1100 COPD (N=12) Control (N=14) SputumMMP-9Concentration(ng/mL) P<0.001
  • 37. 3939 Cathepsins Are Elevated in Smokers 0 1 2 3 4 NS Smoking FS Status S IHCscore * * Nonsmoking Smoking Elias JA, et al, 2006, “State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease: insights from transgenic mice.” Proceedings of the American Thoracic Society, Vol 3:494-498. Official Journal of the American Thoracic Society © American Thoracic Society, Christina Shepherd, Managing Editor, 9/18/08. * P=0.01
  • 38. 4040 Andresen Eet al. PLoS One. 2011;6:e21898. Defensin Gene Is Elevated in COPD and Is Associated With Decreased FEV1 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 healthy controls COPD patients DEFB1mRNAexpression p<0.0001 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 healthy controls COPD 3+4 DEFB1mRNAexpression p<0.0001 COPD 1+2 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 20 DEFB1mRNAexpression Pearson r = -0.43 p = 0.0024 40 60 80 100 120 FEV1 (% predicted) 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 20 DEFB1mRNAexpression Pearson r = -0.49 p = 0.0005 40 60 80 100 120 FEV1/VC ratio (% predicted) p = 0.0014
  • 39. 4141 let-7c MicroRNA Expression and Pulmonary Function Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Pottelberge GR, et al. Am J Respir Crit Care Med. 2011;183:898-906. Official journal of the American Thoracic Society. 7 6 5 4 3 2 Never Smokers COPD ex-smokers relativeexpression(Log2) * 1 0 * Smokers without COPD COPD current smokers * 1250 1000 750 500 250 Never Smokers SputumsTNFR-II(pg/mL) * 0 Current Smokers without COPD COPD current smokers -5 r = -0.43; p = 0.025 -4 -3 -2 -1 2 sputum let-7C 1250 1000 750 500 250 SputumsTNFR-II(pg/mL) 0 0 1 50 75 100 125 150 FEV1 post (% pred) 5 4 3 2 1 relativeexpression(Log2) 0 6
  • 40. 42 COPDforum is supported by Modulation of Inflammation by Histone Deacetylase (HDAC)
  • 41. 4343 Decreased HDAC Expression May Promote Inflammation and Decrease Response to ICS in COPD Normal Histone acetylation Stimuli Steroid sensitive Histone hyperacetylation nitration ubiquitination oxidation ↑TNF ↑IL-8 ↑GM-CSF Stimuli Steroid resistant HAT TF HAT TF TNF IL-8 GM-CSF Glucocorticoid receptor COPD HDAC2 HDAC2 Glucocorticoid peroxynitrite Reproduced from Pharmacol Ther, Vol 116, Ito et al, “Impact of protein acetylation in inflammatory lung diseases,” pp249-265. Copyright © 2007, with permission from Elsevier.
  • 42. 4444 Pulmonary HDAC Levels Decrease With COPD Severity Adapted from Ito K, et al. N Engl J Med. 2005;352:1967-1976. S = COPD Stage 0 .5 1.0 1.5 2.0 Non- smoker N=11 P<0.001 HDAC2expression(vs.laminA/C) P=0.04 P<0.001 P<0.001 S4 N=6 S0 N=9 S1 N=10 S2 N=10 ■ ■ ■ ■ ■
  • 43. 45 COPDforum is supported by Oxidative Stress
  • 44. 4646 Airway Epithelium in COPD: Reactive Oxygen Species and Polymorphonuclear Cells Reproduced from Clin Applied Immunol Rev, Vol 5, Daheshia M, “Pathogenesis of chronic obstructive pulmonary disease (COPD)", pp339-351. Copyright © 2005, with permission from Elsevier. Toxin exposure Alveolar macrophage Mucous secretion Airway epithelium TNF + Neutrophil IL-8, LTB4, MCP-1, MIP-1 Proteinase Connective tissue destruction TNF Macrophage Chemoattraction Oxidant E-Selectin upregulation Tissue damage and Chromatin alteration Proteinase Connective tissue destruction Tissue damage and chromatin alteration Perforin Granzyme TNF Cell death CD8+ T cell + + + + + + + + Oxidant + + + +
  • 45. 4747 Potential Reason for Limited ICS Efficacy in COPD Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Adcock IM, Ito K. Proc Am Thorac Soc. 2005;2:313-319. Official journal of the American Thoracic Society. HDAC2 O2- + NO Unknown kinases Enhanced inflammation  Steroid sensitivity Reduced inflammation  Steroid sensitivity phosphorylation phosphorylationubiquitination phosphatase nitrationPl3K/Akt peroxynitrite Oxidative stress
  • 46. 48 COPDforum is supported by Tissue Destruction and Remodeling
  • 47. 4949 Barnes PJ. N Engl J Med. 2000;343:269-280. Copyright © 2000 Massachusetts Medical Society. All rights reserved. Histopathological Features of COPD Normal lung parenchyma Chronic obstructive bronchiolitis Emphysema
  • 48. 5050 Inflammation Leads to Small Airway Narrowing  Acute and chronic inflammation suspected to contribute to COPD-related small airway narrowing  Airway narrowing leads to airway obstruction  Narrowing results from several factors: – Collagen deposition and increased lymphoid follicles in outer airway wall – Mucosal thickening of airway lumen – Inflammatory exudate in airway lumen Barnes PJ, et al. Eur Respir J. 2003;22: 672-688.
  • 49. 5151 Inflammation and Airway Destruction Normal COPD Reproduced from The Lancet, Vol 364, Hogg JC. "Pathophysiology of airflow limitation in chronic obstructive pulmonary disease," pp709-721. Copyright © 2004, with permission from Elsevier.
  • 50. 5252 Mucous Glands Are Enlarged in COPD Hogg JC. Int J Tuberc Lung Dis. 2008;12:467-479. Reprinted with permission of the International Union Against Tuberculosis and Lung Disease. Copyright © The Union.
  • 51. 5353 Mucous Plugging Obstructs Small Airways in COPD Reproduced from The Lancet, Vol 364, Hogg JC. "Pathophysiology of airflow limitation in chronic obstructive pulmonary disease,” pp709-721. Copyright © 2004, with permission from Elsevier. Normal COPD Mucous Plug
  • 52. 5454 Volume of Airway Wall Tissue Correlates Significantly With Disease Progression Hogg JC, et al. N Engl J Med. 2004;350:2645-2653. Copyright © 2004 Massachusetts Medical Society. All rights reserved. 0 20 40 60 80 100 120 0.25 0.20 0.15 0.10 0.05 0 GOLD Stage 4 FEV1 V:SA(mm) GOLD Stage 3 GOLD Stage 2 GOLD Stages 0 and 1
  • 53. 5555 Apoptotic Pathways in COPD Demedts IK, et al. Respir Res. 2006;7:53. Reproduced with permission from Biomed Central. Survival factor Granzyme B Perforin TNF-α sFasL cytoplasm nucleus ER Stress Apoptosome Apaf 1 Procasp-9 Procasp-9 Casp-9 Casp-8 CAD CAD ICAD Casp-8 Procasp-8Procasp-8 FADDBidtBid Bax Bak Cyt C ER stress DNAfragmentation 1 2 4 3 5 ? Fas
  • 54. 5656 Interaction of Apoptosis and Inflammatory Pathways in COPD MMPs / TIMPsMacrophages Neutrophils Impaired clearance of apoptotic cells Phosphatidylserine receptor CD8+ T-cells Perforins VEGF Epithelial cell injury Survival signals Degradation of BM Activation of FasL Granzyme B OXIDATIVE STRESS INFLAMMATION APOPTOSIS NE NE/1-AT PROTEASE/ANTI-PROTEASE IMBALANCE Demedts IK, et al. Respir Res. 2006;7:53. Reproduced with permission from Biomed Central.
  • 55. 5757 Lim SC, et al. Yonsei Med J. 2011;52:581.587. Permission granted. Apoptotic Lymphocytes and Exacerbation of COPD  Compared to stable COPD, circulating apoptotic lymphocytes, CD 4+ and CD 8+ T cells were significantly increased in patients with exacerbation of COPD.  TNF-α presented a positive correlation with apoptotic lymphocytes in patients with exacerbation of COPD. 30 25 20 15 10 5 Control Lymphocytesapoptosis(%) p<0.001 0 Stable COPD Exacerbation of COPD p<0.001 p=0.015 30 25 20 15 10 5 ControlCD8+ apoptosis(%) p<0.001 0 Stable COPD Exacerbation of COPD p=0.001 p=0.030 30 25 20 15 10 5 Control CD4+ apoptosis(%) p<0.001 0 Stable COPD Exacerbation of COPD p<0.001 p=0.015 300 250 200 150 100 50 Control TNF-α(pg/mL) p<0.001 0 Stable COPD Exacerbation of COPD p=0.021 p<0.001350
  • 56. 5858Elias JA, et al. Proc Am Thorac Soc. 2006;3:494-498. Reproduced with permission from American Thoracic Society. Copyright © 2006 Multiple Pathways Lead to Emphysema in a Murine Model Protease-Antiprotease abnormalities MMP-12 Cathepsins Apoptosis Emphysema Inflammation IFN-/IL-13 Injury
  • 57. 5959 Macroscopic Emphysema
  • 58. 6060 Alveolar Septal Cell Apoptosis and Emphysema Kasahara Y, et al. Am J Respir Crit Care Med. 2001;163:737-744. Reproduced with permission from American Thoracic Society. Copyright © 2001 Increased level of apoptosis Reduced VEGF expression 25 20 15 10 5 0 P<0.02 P<0.01 Nonsmokers Smokers Emphysema No.TUNEL+cells/Nucleicacid(g) P<0.01300 250 200 150 100 50 0 Normal Emphysema N=11 N=12 VEGF(pg/mL) VEGF = Vascular endothelial growth factor.
  • 59. 6161 Saetta M, et al. Am Rev Respir Dis. 1985;132:894-900. Reproduced with permission from American Thoracic Society. Copyright © 1985 The Greater the Airway Inflammation, the Greater the Destruction of Alveolar Attachments 0 20 40 60 80 0 10 15 25 Number of intact attachments Airwayinflammationscore(%) 20 Smokers’ lungs Surgical smokers’ lungs P<0.001 r = –0.80
  • 60. 62 COPDforum is supported by Inflammation in Acute Exacerbations
  • 61. 6363 Exacerbations of Chronic Bronchitis and Inflammatory Cell Types Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652. Maestrelli P, et al. Am J Respir Crit Care Med. 1995;152:1926-1931. Barnes PJ. N Engl J Med. 2000;343:269-280. COPD Exacerbation Eosinophils Eosinophils T-Cells Neutrophils Cells Predominant in: Induced sputum Biopsy Neutrophils
  • 62. 6464 Increase in Neutrophils During COPD Exacerbations  Chronic lower airway bacterial colonisation is common in stable COPD patients1  During exacerbations, bacterial numbers increase in association with an inflammatory response2  Exacerbations may be associated with isolation of new bacterial strains3  Neutrophil products can further impair the mucosal defenses4 1. Monsó E, et al. Am J Respir Crit Care Med. 1995;152:1316-1320. 2. Sethi S, et al. Am J Respir Crit Care J Med. 2007;176:356-361. 3. Sethi S, et al. Am J Respir Crit Care Med. 2004;169:448-453. 4. White AJ, et al. Thorax. 2003;58:73-80.
  • 63. 6565 Exhaled 8-Isoprostane in Exacerbations Reproduced with permission of Thorax from “Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD,” Biernacki et al, Vol 58, Copyright © 2003; permission conveyed through Copyright Clearance Center, Inc. Treated with antibiotics Exhaled8-isoprostane(pg/mL) FEV1 51% predicted P<0.0001 0 5 10 15 20 25 Exacerbation 2 weeks Normal n=21 subjects n=12
  • 64. 6666 Increased Neutrophils During Exacerbations of Chronic Bronchitis * P<0.01 versus stable disease Adapted from Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652. Exacerbations * Stable disease 300 0 250 200 100 150 50
  • 65. 6767 Increased Eosinophils During Exacerbations of Chronic Bronchitis * P<0.001 Adapted from Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652. 60% 150 100 50 * EG2(+)cells/mm2 0 200 ExacerbationsStable disease
  • 66. 6868 1.55 4 3.25 15.6 0 2 4 6 8 10 12 14 16 18 IL-6 (pg/mL) CRP (g/dL) Baseline Exacerbation Elevation of Serum Markers for Systemic Inflammation in Acute Exacerbations Adapted from Hurst JR, et al. Am J Respir Crit Care Med. 2006;174:867-874. * P<0.001 versus baseline * Serumconcentration *
  • 67. 6969 MMP-9 Is Elevated in Acute Exacerbations Mercer PF, et al. Respir Res. 2005;6:151. Reproduced with permission from Biomed Central. P<0.01 MMP-9(µg/gsputum) Pre-exacerbation 0 20 40 60 80 100 Sputum Sample 120 140 Exacerbation
  • 68. 70 COPDforum is supported by Clinical Consequences of Inflammation
  • 69. 7171 Telomere Dysfunction Results in Sustained Inflammation in COPD  In situ lung specimen studies showed a higher percentage of senescent pulmonary vascular endothelial cells stained for p16 and p21 in patients with COPD than in control subjects Adapted from Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356. p16 p21 Arrowheads show p16- and p21-positive cells. Scale bar = 25 μm * P<0.0001 0 20 40 60 80 100 %ofp16positivecells/ VWFpositivecells Controls COPD * 0 20 40 60 80 %p21positivecells/ VWFposiitivecells Controls COPD *
  • 70. 7272 Telomere Dysfunction Results in Sustained Inflammation in COPD  Telomerase activity was detectable only at early cell passages and was significantly lower in patients with COPD than in control subjects at passage 4 Adapted from Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356. The T/S ratio is the ratio of telomere repeatcopy numberoversingle gene copynumber. * P<0.05 versus controland † P<0.05 versus correspondingvalue atpassage 4 Passage 4 Telomerelength(T/S)ratio Controls COPD 1.5 1.0 0.5 0.0 Senescence * † †
  • 71. 7373 Decreased Replicative Capacity of Pulmonary Vascular Endothelial Cells From Patients With COPD Adapted from Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356. * P<0.01PDL = population doublinglevel Controls COPD CumulativePDL 25 20 15 0 * 5 10 P4 CumulativePDL 25 20 15 0 5 10 P6 P8 P10 P12 P14 P16 P18 Controls COPD
  • 72. 7474 Levels of Cytokines Are Increased in Pulmonary Vascular Endothelial Cells From Patients With COPD Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356. Official journal of the American Thoracic Society. *P<0.05 and ***P<0.0001 versus control values; † P<0.05 and †† P<0.01 versus corresponding value at passage 6. FGF-2 = fibroblast growth factor-2; MCP-1 = monocyte chemotactic factor-1; PAI-1 = plasminogen activator inhibitor-1; PDGF = platelet-derived growth factor; RANTES = regulated upon activation, normal T-cell expressed and secreted; sICAM-1 = soluble intercellular adhesion molecule-1. 100 6000 10 80 60 40 20 Passage 6 IL6pg/mL 0 * Senescene † 4000 2000 Passage 6 MCP-1pg/mL 0 *** Senescene † 4 2 Passage 6 0 * Senescene †† 6 8 sICAM-1ng/mL †† 5000 4000 3000 2000 1000 Passage 6 IL8pg/mL 0 * Senescene † 15 10 5 Passage 6 RANTESpg/mL 0 Senescene † † 6000 4000 2000 Passage 6 PDGFng/mL 0 Senescene † Controls COPD
  • 73. 7575 Levels of Cytokines Are Increased in Pulmonary Vascular Endothelial Cells From Patients With COPD *P<0.05 and ***P<0.0001 versus control values; † P<0.05 and †† P<0.01 versus corresponding value at passage 6. FGF-2 = fibroblast growth factor-2; MCP-1 = monocyte chemotactic factor-1; PAI-1 = plasminogen activator inhibitor-1; PDGF = platelet-derived growth factor; RANTES = regulated upon activation, normal T-cell expressed and secreted; sICAM-1 = soluble intercellular adhesion molecule-1. 800 600 400 200 Passage 6 Hu-GROpg/mL 0 * Senescene † 250 150 100 Passage 6 PAI-1pg/mL 0 Senescene † † 25 15 5 Passage 6 FGF-2pg/mL 0 Senescene 200 50 20 10 * Controls COPD Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356. Official journal of the American Thoracic Society.
  • 74. 7676 Inflammation Predicts Mortality in Patients With COPD Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Celli BR, et al. Am J Respir Crit Care Med. 2012;185:1065-1072. Official journal of the American Thoracic Society. 100% 95% 90% 85% 80% 75% 0 6 12 18 24 30 36 IL-6 <4.5 pg/mL (n=1462) IL-6 >4.5 pg/mL (n=504) p<0.001 IL -6 100% 95% 90% 85% 80% 75% 0 6 12 18 24 30 36 Neutrophils <5.8x10^9/L (n=1386) Neutrophils >5.8x10^9/L (n=593) p<0.001 Neutrophils 100% 95% 90% 85% 80% 75% 0 6 12 18 24 30 36 Fibrinogen <518 mg/dL (n=1534) Fibrinogen >518 mg/dL (n=490) p<0.001 Fibrinogen Time Observed (Months) PercentSurvival
  • 75. 7777 Inflammation Predicts Mortality in Patients With COPD 100% 95% 90% 85% 80% 75% 0 6 12 18 24 30 36 hsCRP <8.7 pg/mL (n=1572) hsCRP >8.7 mg/dL (n=404) p<0.001 hsCRP 100% 95% 90% 85% 80% 75% 0 6 12 18 24 30 36 CCL-18 <153 ng/mL (n=1432) CCL-18 >153 ng/mL (n=278) p<0.001 CCL-18/PARC 100% 95% 90% 85% 80% 75% 0 6 12 18 24 30 36 SP-D <165 ng/mL (n=1461) SP-D >165 ng/mL (n=524) p<0.001 SP-D Time Observed (Months) PercentSurvival Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Celli BR, et al. Am J Respir Crit Care Med. 2012;185:1065-1072. Official journal of the American Thoracic Society.
  • 76. 7878 Progression From Molecular to Clinical Events in COPD Inflammation Chung KF, et al. Eur Respir J. 2008;31:1334-1356. Aetiology Cigarette smoke Environmental pollutants Amplifying processes • Innate immunity • Acquired immunity • Oxidative stress • Stress response • Cellularactivation • Extrapulmonary effects • Somatic mutations • Genetics • Epigenetics Cellular processes • Inflammatory cell recruitment/ activation • T-cell activation • Autoimmunity • Transcriptional activation • Mediatorrelease • Tissue repair • Apoptosis • Cell proliferation • Senescence • Systemic Inflammation • Skeletalmuscle Death GOLD stage IV: severe Exacerbations Mild Asymptomatic Clinical outcomes • Mucousgland hyperplasia • Small airways obstruction • Centrilobular emphysema • Corticosteroid resistance • Bacterial colonisation • Respiratoryvirus infections Pathological processes
  • 77. 7979 Clinical Impact of Inflammation in COPD Tsoumakidou M, et al. Respir Res. 2006;7:80. Reproduced with permission from Biomed Central. Increased Airway Inflammation Increased mucous production Airway wall thickening Airway wall oedema Bronchoconstriction Airway narrowing V’/Q’ MismatchingHyperinflation Worsening of gas exchange Increased work of breathing Increased oxygen consumption – Decreased mixed venous oxygen Cough, sputum, dyspnoea, Respiratory failure
  • 78. 8080 Inflammation: Clinical Consequences Systemic  Nutritional abnormalities and weight loss  Hypoxaemia  Skeletal muscle dysfunction  Cardiovascular disease  Depression  Osteoporosis  Anaemia Agusti AG, et al. Eur Respir J. 2003;21:347-360. Agusti AG. Proc Am Thorac. 2006;3:478-483. Barnes PJ, Cell BR. Eur Respir J. 2009;33:1165-1185. Pulmonary  Dyspnoea  Cough  Sputum production  Exacerbations
  • 79. Influencing the bronchial tone Inhibitory NANC (iNANC) system is considered to be the main neural mechanism mediating ASM relaxation by releasing of vasoactive intestinal peptide (VIP), VIP structure-related peptides and nitric oxide (NO) . On the other hand, excitatory NANC (eNANC) system mediates bronchial contraction activating the efferent functions of bronchopulmonary-sensitive sensory nerves. These nerves release tachykinins, such as substance P and neurokinin A, which in turn activate neurokinin-1 (NK-1) and NK-2 receptors located on the ASM membrane, thus inducing bronchoconstriction
  • 80. Influencing the bronchial tone Bronchodilation may, therefore, be obtained either by directly relaxing the smooth muscle through stimulation of the b2-AR with b2-AR agonists, or/and by inhibiting the action of ACh at mAChRs. Furthermore, an alternative approach could be the modulation of the NANC system.
  • 81. Bronchodilators Indacterol Olodaterol Vilanterol Glycopyrronium bromide Aclidinium bromide Xanthines
  • 82. Influencing The Cellular Components Of Inflammation Phosphodiesterase Inhibitors The PDE4 isoenzyme is a major therapeutic target because it is the predominant isoenzyme in the majority of inflammatory cells, including neutrophils, which are implicated in the pathogenesis of COPD. Inhibition of PDE4 in inflammatory cells influences various specific responses, such as the production and/or release of pro- inflammatory mediators including cytokines and active oxygen species , with a well-documented efficacy in animal models of COPD .
  • 83. Influencing The Cellular Components Of Inflammation Phosphodiesterase Inhibitors Oral PDE4 inhibitors: roflumilast; GRC-3886; ELB353; GRC 4039; MEM1414; oglemilast; OX914; ASP3258; TAS-203; Zl-n-91; NIS- 62949; tetomilast Inhaled PDE4 inhibitors; GSK256066; SCH900182; Compound 1; tofimilast; AWD12-281; UK500001 PDE3/4 inhibitors: RPL554 PDE4/7 inhibitors: TPI 1100
  • 84. Influencing The Cellular Components Of Inflammation Adenosine receptors Agonist Some evidence suggests the involvement of adenosine receptors in inflammation. Four subtypes (A1, A2A, A2B, A3) of adenosine receptors have been characterized. The anti- inflammatory effect of adenosine is due to a short-term activation of A2A receptor that elevates cAMP and, consequently, modulates key pro-inflammatory neutrophil functions such as superoxide generation, degranulation and adhesion. Furthermore, adenosine A2A receptor activation induces a shift in the profile of lipid mediator production from leukotrienes to prostaglandin E2.This shift may contribute to prevent the subsequent neutrophil-elicited inflammatory events
  • 85. Influencing The Cellular Components Of Inflammation Adenosine receptors A2a Agonists CGS21680; ATL146e; UK371,104; GW328267X; regadenoson (CVT-3146); 2-(cyclohexylethylthio)-AMP
  • 86. Influencing The Cellular Components Of Inflammation Adhesion molecules Inflammatory processes in COPD are coupled to an increased recruitmentof neutrophilsto the lung in response to a release of IL-8 and leukotriene B4 (LTB4) by activated epithelial cells and macrophages . Migration of inflammatory cells from the vascular compartment to the surrounding tissue is partly regulated by selectins (L-, P- and E-selectin). Selectins mediate transient adhesive interactions pertinent to inflammation through the recognition of the carbohydrate epitope, sialyl Lewisx (sLex), expressed on circulating leukocytes. The rapid turnover of selectin--ligand bonds mediates the cell tethering and rolling in shear flow. Several studies suggest that selectins are involved in the inflammatory processes of COPD . Therefore, targeting these molecules might reduce the inflammation in COPD
  • 87. Influencing The Cellular Components Of Inflammation Drugs that interfere with adhesion molecules Carbohydrate-based inhibitors: sLex antagonists (bimosiamose); heparins and heparinoids (PGX- 100, PGX-200); synthetic glycomimetic molecule (GMI-1070) mAb inhibitors: EL246
  • 88. Influencing The Inflammatory mediators 1-TNF-a 2-Chemokines 3-NF-kB 4-p38 MAPK and MK2 5-PI3K 6-LTB4 7-PPAR
  • 89. Targeting protease activity at the enzymatic level
  • 90. Drugs that may have indirect anti- inflammatory actions Reversing glucocorticoid resistance : Activation of HDAC2: theophylline; curcumin; resveratrol Inhibition of P-glycoprotein Inhibition of MIF