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COPD First Session

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Gamal Agmy

This document provides an overview of COPD (chronic obstructive pulmonary disease). It defines COPD and discusses its burden, risk factors, pathology, and history. It notes that COPD is characterized by airflow limitation caused by an inflammatory response in the lungs to noxious particles. The document outlines the learning objectives which are to understand COPD definition, burden, risk factors, and pathogenesis. It also discusses the prevalence of COPD internationally, underdiagnosis in the US, and the economic and social burden of the disease.

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COPD First Session
COPD Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university
COPD First Session
Goal of this learning modules •To Provide a framework to make informed decisions regarding the diagnosis and treatment of Chronic obstructive pulmonary disease
Learning objectives After completing this module you should know: •know the definition of COPD •Understand the burden of COPD •know the risk factors of COPD occurrence •Learn about the pathology, pathogenesis and Pathophysiology of COPD.
History of COPD •A British medical textbook (1860s )→ C/P of chronic bronchitis as an advanced disease with repeated bronchial infections that ended in right-sided heart failure. •20th century, Ciba symposium of 1958 proposed definitions of chronic bronchitis and emphysema → concept of airflow obstruction. •Chronic bronchitis: chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded). •Emphysema: an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis
Definition & Overview Common preventable & treatable disease Characterized by persistent airflow limitation that is usually progressive Associated with an enhanced chronic inflammatory response in the airways & the lung to noxious particles or gases Exacerbations & comorbidities contribute to the overall severity in individual patients
COPD is a progressive disease The Downward Spiral in COPD
Burden of COPD COPD is a leading cause of morbidity & mortality worldwide The burden will increase in coming decades due to continued exposure to risk factors & the aging of the world’s population COPD is associated with significant economic burden
Prevalence Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population- based prevalence study. Lancet. 2007;370:741-750. 11.8% 8.5% 10.1% overall
COPD Misdiagnosis Is Common in Women Chapman KR, Tashkin DP, Pye DJ. Gender bias in the diagnosis of COPD. Chest. 2001;119:1691-1695
Under diagnosis of COPD in the United States • Over 12 million people in the United States have been diagnosed with COPD; another 12 million are estimated to be undiagnosed1 • Data from NHANES III indicate that approximately 24 million US adults have evidence of impaired lung function indicative of COPD2,3 • Most (70%) of patients with undiagnosed COPD are <65 years 70% <Age 65 30% ≥Age 65 Percent With Undiagnosed COPD 1. NHLBI; available at http://www.nhlbi.nih.gov/health/public/lung/copd/index.html. 3. Mannino DM, et al. Proc Am Thorac Soc. 2007;4:502-306 2. Mannino DM, et al. MMWR Surveill Summ. 2002;51:1-16.
Mortality : Global burden of Disease study: COPD rank Murray and Lopez Lancet 1997
Mortality : Global burden of Disease study: COPD rank
Mortality : Global burden of Disease study •Almost 90% of COPD deaths occur in low- and middle-income countries.
Economic and social burden Economic •USA: Direct costs $ 29.5 billion & Indirect costs $ 20.4 billion •Europe: 38.6 billion Euros •In developing countries: –Workplace & home productivity loss > Medical costs loss Social •Disability-Adjusted Life year (DALY) –1990→ 12th leading cause of DALYs –2030 → 7th leading cause of DALYs
Risk factors for COPD Influence disease development & progression
Genes •Gene-environmental interaction are the key for development of COPD. •Susceptibility to COPD is not dichotomous variable and a range of susceptibility exits. –Some smokers develop the disease earlier than others. –Progression in COPD is very heterogeneous
Genes •In patients with COPD –emphysema represents accelerated ageing of the lung –studies showed telomere shortening & dysfunction •Telomerase null mice with short telomeres –increased emphysema –double-strand DNA breaks •after exposure to chronic cigarette smoke •with evidence of reduced epithelial repair •Family with a telomerase mutation –have early-onset emphysema
Cumulative exposure to noxious particles is the key risk factor for COPD
Airway Responsiveness-Dutch Hypothesis •Increased airways responsiveness and allergy are clinical phenotypes that predict increased susceptibility to cigarette smoke. •Methacholine and histamine responsiveness precedes and predicts accelerated decline in lung function, thus a risk factor for COPD.* •Increased airways responsiveness noted among 1st degree relatives of patients with early onset COPD.^ *Silva, GE et al. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004; 126:59. ^Celedon JC et al. Bronchodilator responsiveness and serum total IgE levels in families of probands with severe early-onset COPD. Eur Respir J 1999; 14:1009.
Pathogenesis Noxious agents Biomass particles Occupational agents Pollutants Genetic factors Resp. infection
These data are communicated for scientific purpose only. Confidential slide set 23 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-8 Procasp-8 FADD Bid tBid Bax Bak Cyt C ER stress DNA fragmentation 1 2 4 3 5 ? Fas COPD Pathogenesis
These data are communicated for scientific purpose only. Confidential slide set
These data are communicated for scientific purpose only. Confidential slide set 25 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 COPD Pathogenesis
These data are communicated for scientific purpose only. Confidential slide set 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 Siafakas NM, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:453-462. COPD Pathogenesis
Pathogenesis Obstructive Bronchiolitis Emphysema
These data are communicated for scientific purpose only. Confidential slide set Inflammatory Cells in Stable COPD Gamal Agmy 2-5-2014 Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 29 Neutrophils in COPD Mucous hypersecretion 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. Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 30 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 Neutrophils in iInduced sputum (%) 90 20 – 30 80 60 70 50 40 FEV1 decline (mL/year) P<0.01 Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 31 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 Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 32 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 Morphology Tunel NS HS COPD 60 50 40 30 20 10 0 Apoptotic neutrophils [%] Image courtesy of R Buhl. NS: nonsmoking controls (n=9) HS: healthy smoking controls (n=9) TUNEL: the terminal transferase- mediated dUTP nick end-labeling method Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 33 Alveolar Macrophages in COPD  Phagocytosis Cigarette smoke Wood smoke Elastolysis MMP-9, MMP-12 Cathepsins K, L, S Emphysema Steroid resistance NO ONOO- ROS  HDAC  Steroid response Monocytes MCP-1 GRO- Neutrophils LTB4 IL-8 GRO- CD8+ Cells IP-10 Mig I-TAC Adapted f rom Barnes PJ. J COPD. 2004;1:59-70. Copyright © 2004 f rom "Alveolar Macrophages as Orchestrators of COPD" by Barnes. Reproduced by permission of Taylor & Francis Group, LLC., www.taylorandf rancis.com Emphysema Severe emphysema Images courtesy of R Buhl.  Numbers  Secretion Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 34 Inflammatory Mediators in COPD – Summary Cell Neutrophils Macrophages T-cell Epithelial cell 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. Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 35 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 Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 36 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 proinflammatory molecules e.g. VCAM-1, ICAM-1 and RAGE Subcellular ROS production TNF- Antioxidants e.g. GSH, Catalase Scavenge free radicals, detoxify cellular hydrogen peroxide and inhibit ROS generation Proinflammation + + + + + + + - - Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set Modulation of Inflammation by Histone Deacetylase (HDAC) Inflammation in COPD Gamal Agmy 2-5-2014
These data are communicated for scientific purpose only. Confidential slide set 38 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 f rom Pharmacol Ther, Vol 116, Ito et al, “Impact of protein acetylation in inf lammatory lung diseases,” pp249-265. Copyright © 2007, with permission f rom Elsevier. Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 39 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 HDAC2 expression (vs. lamin A/C) P=0.04 P<0.001 P<0.001 S4 N=6 S0 N=9 S1 N=10 S2 N=10 ■ ■ ■ ■ ■ Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 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. Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 41 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. Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 42 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 Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 43 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’ Mismatching Hyperinflation Worsening of gas exchange Increased work of breathing Increased oxygen consumption – Decreased mixed venous oxygen Cough, sputum, dyspnoea, Respiratory failure Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 44 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 Inflammation in COPD
Inflammatory cells and mediators in COPD
Pathogenesis
The site of pathology in COPD Mucus gland hyperplasiaGoblet cellhyperplasiaMucus hypersecretionNeutrophilsin sputumSquamousmetaplasiaof epithelium↑MacrophagesNo basement membrane thickeningLittle increase inairway smooth muscle↑CD8+lymphocytesChanges in Large Airways of COPD PatientsChanges Patients Source: Peter J. Barnes, MD
Chronic bronchitis Hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells
The site of pathology in COPD Disrupted alveolar attachmentsInflammatory exudatein lumenPeribronchialfibrosisLymphoid follicleThickened wall with inflammatory cells-macrophages, CD8+ cells, fibroblastsChanges in Small Airways in COPD Patients Source: Peter J. Barnes, MD
The site of pathology in COPD Endothelial dysfunctionIntimalhyperplasiaSmooth muscle hyperplasia↑Inflammatory cells(macrophages, CD8+lymphocytes) Changes in Pulmonary Arteries in COPD Patients Source: Peter J. Barnes, MD
The site of pathology in COPD
Emphysema
Emphysema •Centriacinar –Focal destruction limited to the respiratory bronchioles and the central portions of the acini. –associated with cigarette smoking –most severe in the upper lobes •Panacinar –involves the entire alveolus distal to the terminal bronchiole. –most severe in the lower lung zones –AAT deficiency •Distal acinar or paraseptal –least common form and involves distal airway structures, alveolar ducts, and sacs. loss of alveolar walls and dilatation of airspaces in emphysema
Natural History of Emphysema •In non-smokers, maximal lung function –attained at age 15 - 25 years –after a variable plateau phase, declines ~ 20 -25 mL/year •Lung Health Study (large longitudinal study) –smoking is associated with an accelerated decline in lung function •Females are at higher risk of lung damage –related to smoke exposure than males
Fletcher C et al. 1977 FEV1 (% of value at age 25) 100 25 50 75 Never smoked or not susceptible to smoke Age (years) Disability Smoked regularly and susceptible to its effects Death 0 25 50 75 Stopped at 65 Stopped at 45 Classical View of “Disease Progression” & “Disease Modification”
Pathogenic mechanisms Pathological changes in COPD Physiological abnormalities: Mucous hypersecretion & ciliary dysfunction Airflow obstruction & hyperinflation Gas exchange abnormalities Pulmonary hypertension & systemic effects Pathophysiology
Spectrum of COPD
Thank you

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COPD First Session

  • 2. COPD Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university
  • 4. Goal of this learning modules •To Provide a framework to make informed decisions regarding the diagnosis and treatment of Chronic obstructive pulmonary disease
  • 5. Learning objectives After completing this module you should know: •know the definition of COPD •Understand the burden of COPD •know the risk factors of COPD occurrence •Learn about the pathology, pathogenesis and Pathophysiology of COPD.
  • 6. History of COPD •A British medical textbook (1860s )→ C/P of chronic bronchitis as an advanced disease with repeated bronchial infections that ended in right-sided heart failure. •20th century, Ciba symposium of 1958 proposed definitions of chronic bronchitis and emphysema → concept of airflow obstruction. •Chronic bronchitis: chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded). •Emphysema: an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis
  • 7. Definition & Overview Common preventable & treatable disease Characterized by persistent airflow limitation that is usually progressive Associated with an enhanced chronic inflammatory response in the airways & the lung to noxious particles or gases Exacerbations & comorbidities contribute to the overall severity in individual patients
  • 8. COPD is a progressive disease The Downward Spiral in COPD
  • 9. Burden of COPD COPD is a leading cause of morbidity & mortality worldwide The burden will increase in coming decades due to continued exposure to risk factors & the aging of the world’s population COPD is associated with significant economic burden
  • 10. Prevalence Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population- based prevalence study. Lancet. 2007;370:741-750. 11.8% 8.5% 10.1% overall
  • 11. COPD Misdiagnosis Is Common in Women Chapman KR, Tashkin DP, Pye DJ. Gender bias in the diagnosis of COPD. Chest. 2001;119:1691-1695
  • 12. Under diagnosis of COPD in the United States • Over 12 million people in the United States have been diagnosed with COPD; another 12 million are estimated to be undiagnosed1 • Data from NHANES III indicate that approximately 24 million US adults have evidence of impaired lung function indicative of COPD2,3 • Most (70%) of patients with undiagnosed COPD are <65 years 70% <Age 65 30% ≥Age 65 Percent With Undiagnosed COPD 1. NHLBI; available at http://www.nhlbi.nih.gov/health/public/lung/copd/index.html. 3. Mannino DM, et al. Proc Am Thorac Soc. 2007;4:502-306 2. Mannino DM, et al. MMWR Surveill Summ. 2002;51:1-16.
  • 13. Mortality : Global burden of Disease study: COPD rank Murray and Lopez Lancet 1997
  • 14. Mortality : Global burden of Disease study: COPD rank
  • 15. Mortality : Global burden of Disease study •Almost 90% of COPD deaths occur in low- and middle-income countries.
  • 16. Economic and social burden Economic •USA: Direct costs $ 29.5 billion & Indirect costs $ 20.4 billion •Europe: 38.6 billion Euros •In developing countries: –Workplace & home productivity loss > Medical costs loss Social •Disability-Adjusted Life year (DALY) –1990→ 12th leading cause of DALYs –2030 → 7th leading cause of DALYs
  • 17. Risk factors for COPD Influence disease development & progression
  • 18. Genes •Gene-environmental interaction are the key for development of COPD. •Susceptibility to COPD is not dichotomous variable and a range of susceptibility exits. –Some smokers develop the disease earlier than others. –Progression in COPD is very heterogeneous
  • 19. Genes •In patients with COPD –emphysema represents accelerated ageing of the lung –studies showed telomere shortening & dysfunction •Telomerase null mice with short telomeres –increased emphysema –double-strand DNA breaks •after exposure to chronic cigarette smoke •with evidence of reduced epithelial repair •Family with a telomerase mutation –have early-onset emphysema
  • 20. Cumulative exposure to noxious particles is the key risk factor for COPD
  • 21. Airway Responsiveness-Dutch Hypothesis •Increased airways responsiveness and allergy are clinical phenotypes that predict increased susceptibility to cigarette smoke. •Methacholine and histamine responsiveness precedes and predicts accelerated decline in lung function, thus a risk factor for COPD.* •Increased airways responsiveness noted among 1st degree relatives of patients with early onset COPD.^ *Silva, GE et al. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004; 126:59. ^Celedon JC et al. Bronchodilator responsiveness and serum total IgE levels in families of probands with severe early-onset COPD. Eur Respir J 1999; 14:1009.
  • 22. Pathogenesis Noxious agents Biomass particles Occupational agents Pollutants Genetic factors Resp. infection
  • 23. These data are communicated for scientific purpose only. Confidential slide set 23 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-8 Procasp-8 FADD Bid tBid Bax Bak Cyt C ER stress DNA fragmentation 1 2 4 3 5 ? Fas COPD Pathogenesis
  • 24. These data are communicated for scientific purpose only. Confidential slide set
  • 25. These data are communicated for scientific purpose only. Confidential slide set 25 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 COPD Pathogenesis
  • 26. These data are communicated for scientific purpose only. Confidential slide set 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 Siafakas NM, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:453-462. COPD Pathogenesis
  • 28. These data are communicated for scientific purpose only. Confidential slide set Inflammatory Cells in Stable COPD Gamal Agmy 2-5-2014 Inflammation in COPD
  • 29. These data are communicated for scientific purpose only. Confidential slide set 29 Neutrophils in COPD Mucous hypersecretion 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. Inflammation in COPD
  • 30. These data are communicated for scientific purpose only. Confidential slide set 30 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 Neutrophils in iInduced sputum (%) 90 20 – 30 80 60 70 50 40 FEV1 decline (mL/year) P<0.01 Inflammation in COPD
  • 31. These data are communicated for scientific purpose only. Confidential slide set 31 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 Inflammation in COPD
  • 32. These data are communicated for scientific purpose only. Confidential slide set 32 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 Morphology Tunel NS HS COPD 60 50 40 30 20 10 0 Apoptotic neutrophils [%] Image courtesy of R Buhl. NS: nonsmoking controls (n=9) HS: healthy smoking controls (n=9) TUNEL: the terminal transferase- mediated dUTP nick end-labeling method Inflammation in COPD
  • 33. These data are communicated for scientific purpose only. Confidential slide set 33 Alveolar Macrophages in COPD  Phagocytosis Cigarette smoke Wood smoke Elastolysis MMP-9, MMP-12 Cathepsins K, L, S Emphysema Steroid resistance NO ONOO- ROS  HDAC  Steroid response Monocytes MCP-1 GRO- Neutrophils LTB4 IL-8 GRO- CD8+ Cells IP-10 Mig I-TAC Adapted f rom Barnes PJ. J COPD. 2004;1:59-70. Copyright © 2004 f rom "Alveolar Macrophages as Orchestrators of COPD" by Barnes. Reproduced by permission of Taylor & Francis Group, LLC., www.taylorandf rancis.com Emphysema Severe emphysema Images courtesy of R Buhl.  Numbers  Secretion Inflammation in COPD
  • 34. These data are communicated for scientific purpose only. Confidential slide set 34 Inflammatory Mediators in COPD – Summary Cell Neutrophils Macrophages T-cell Epithelial cell 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. Inflammation in COPD
  • 35. These data are communicated for scientific purpose only. Confidential slide set 35 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 Inflammation in COPD
  • 36. These data are communicated for scientific purpose only. Confidential slide set 36 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 proinflammatory molecules e.g. VCAM-1, ICAM-1 and RAGE Subcellular ROS production TNF- Antioxidants e.g. GSH, Catalase Scavenge free radicals, detoxify cellular hydrogen peroxide and inhibit ROS generation Proinflammation + + + + + + + - - Inflammation in COPD
  • 37. These data are communicated for scientific purpose only. Confidential slide set Modulation of Inflammation by Histone Deacetylase (HDAC) Inflammation in COPD Gamal Agmy 2-5-2014
  • 38. These data are communicated for scientific purpose only. Confidential slide set 38 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 f rom Pharmacol Ther, Vol 116, Ito et al, “Impact of protein acetylation in inf lammatory lung diseases,” pp249-265. Copyright © 2007, with permission f rom Elsevier. Inflammation in COPD
  • 39. These data are communicated for scientific purpose only. Confidential slide set 39 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 HDAC2 expression (vs. lamin A/C) P=0.04 P<0.001 P<0.001 S4 N=6 S0 N=9 S1 N=10 S2 N=10 ■ ■ ■ ■ ■ Inflammation in COPD
  • 40. These data are communicated for scientific purpose only. Confidential slide set 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. Inflammation in COPD
  • 41. These data are communicated for scientific purpose only. Confidential slide set 41 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. Inflammation in COPD
  • 42. These data are communicated for scientific purpose only. Confidential slide set 42 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 Inflammation in COPD
  • 43. These data are communicated for scientific purpose only. Confidential slide set 43 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’ Mismatching Hyperinflation Worsening of gas exchange Increased work of breathing Increased oxygen consumption – Decreased mixed venous oxygen Cough, sputum, dyspnoea, Respiratory failure Inflammation in COPD
  • 44. These data are communicated for scientific purpose only. Confidential slide set 44 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 Inflammation in COPD
  • 45. Inflammatory cells and mediators in COPD
  • 47. The site of pathology in COPD Mucus gland hyperplasiaGoblet cellhyperplasiaMucus hypersecretionNeutrophilsin sputumSquamousmetaplasiaof epithelium↑MacrophagesNo basement membrane thickeningLittle increase inairway smooth muscle↑CD8+lymphocytesChanges in Large Airways of COPD PatientsChanges Patients Source: Peter J. Barnes, MD
  • 48. Chronic bronchitis Hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells
  • 49. The site of pathology in COPD Disrupted alveolar attachmentsInflammatory exudatein lumenPeribronchialfibrosisLymphoid follicleThickened wall with inflammatory cells-macrophages, CD8+ cells, fibroblastsChanges in Small Airways in COPD Patients Source: Peter J. Barnes, MD
  • 50. The site of pathology in COPD Endothelial dysfunctionIntimalhyperplasiaSmooth muscle hyperplasia↑Inflammatory cells(macrophages, CD8+lymphocytes) Changes in Pulmonary Arteries in COPD Patients Source: Peter J. Barnes, MD
  • 51. The site of pathology in COPD
  • 53. Emphysema •Centriacinar –Focal destruction limited to the respiratory bronchioles and the central portions of the acini. –associated with cigarette smoking –most severe in the upper lobes •Panacinar –involves the entire alveolus distal to the terminal bronchiole. –most severe in the lower lung zones –AAT deficiency •Distal acinar or paraseptal –least common form and involves distal airway structures, alveolar ducts, and sacs. loss of alveolar walls and dilatation of airspaces in emphysema
  • 54. Natural History of Emphysema •In non-smokers, maximal lung function –attained at age 15 - 25 years –after a variable plateau phase, declines ~ 20 -25 mL/year •Lung Health Study (large longitudinal study) –smoking is associated with an accelerated decline in lung function •Females are at higher risk of lung damage –related to smoke exposure than males
  • 55. Fletcher C et al. 1977 FEV1 (% of value at age 25) 100 25 50 75 Never smoked or not susceptible to smoke Age (years) Disability Smoked regularly and susceptible to its effects Death 0 25 50 75 Stopped at 65 Stopped at 45 Classical View of “Disease Progression” & “Disease Modification”
  • 56. Pathogenic mechanisms Pathological changes in COPD Physiological abnormalities: Mucous hypersecretion & ciliary dysfunction Airflow obstruction & hyperinflation Gas exchange abnormalities Pulmonary hypertension & systemic effects Pathophysiology