1. lobal Initiative for Chronic bstructive ung isease GOLDGOLD GOLDGOLD

2. GOLD Structure GOLD Executive Committee Sonia Buist, MD – Chair Roberto Rodriguez-Roisin, MD – Co-Chair GOLD Executive Committee Sonia Buist, MD – Chair Roberto Rodriguez-Roisin, MD – Co-Chair Science Committee Klaus Rabe, MD, PhD - Chair Science Committee Klaus Rabe, MD, PhD - Chair Dissemination/Implementation Task Group Christine Jenkins, MD - Chair Dissemination/Implementation Task Group Christine Jenkins, MD - Chair

3. GOLD Executive Committee S. Buist, Chair, US A. Anzueto, US ATS P. Calverley, UK T. DeGuia, Philippines Y. Fukuchi, Japan APSR C. Jenkins, Australia J. Kiley, US NHLBI A. Kocabas, Turkey S. Buist, Chair, US A. Anzueto, US ATS P. Calverley, UK T. DeGuia, Philippines Y. Fukuchi, Japan APSR C. Jenkins, Australia J. Kiley, US NHLBI A. Kocabas, Turkey N. Khaltaev, Switzerland WHO M. Lopez, Uruguay ALAT E. Nizankowska, Poland K. Rabe, Netherlands R. Rodriguez-Roisin, Spain T. van der Molen, Netherlands C. Van Weel, Netherlands WONCA

4. GOLD Science Committee K. Rabe, Chair A. Agusti, A. Anzueto P. Barnes S. Buist P. Calverley K. Rabe, Chair A. Agusti, A. Anzueto P. Barnes S. Buist P. Calverley M. Decramer Y. Fukuchi P. Jones R. Rodriguez-Roisin J. Vestbo J. Zielinski

5. Evidence Category Sources of Evidence A Randomized controlled trials (RCTs). Rich body of data B Randomized controlled trials (RCTs). Limited body of data C Nonrandomized trials Observational studies. D Panel consensus judgment Description of Levels of Evidence

6. GOLD Structure GOLD Executive Committee Sonia Buist, MD – Chair Roberto Rodriguez-Roisin, MD – Co-Chair GOLD Executive Committee Sonia Buist, MD – Chair Roberto Rodriguez-Roisin, MD – Co-Chair Science Committee Klaus Rabe, MD, PhD - Chair Science Committee Klaus Rabe, MD, PhD - Chair Dissemination/Implementation Task Group Christine Jenkins, MD - Chair Dissemination/Implementation Task Group Christine Jenkins, MD - Chair GOLD National Leaders - GNL

7. United States United Kingdom Argentina Australia Brazil Austria Canada Chile Belgium China Denmark Columbia Croatia Egypt Germany Greece Ireland Italy Syria Hong Kong ROC Japan Iceland India Korea Kyrgyzstan Uruguay Moldova Nepal Macedonia Malta Netherlands New Zealand Poland Norway Portugal Georgia Romania Russia Singapore Slovakia Slovenia Saudi Arabia South Africa Spain Sweden Thailand Switzerland Ukraine United Arab Emirates Taiwan ROC Venezuela Vietnam Peru Yugoslavia Albania Bangladesh France Mexico Turkey Czech Republic Pakistan Israel GOLD National Leaders Philippines

8. GOLD Website Address http://www.goldcopd.org

9. lobal Initiative for Chronic bstructive ung isease GOLDGOLD GOLDGOLD

10. GOLD Objectives n Increase awareness of COPD among health professionals, health authorities, and the general public. n Improve diagnosis, management and prevention of COPD. n Stimulate research in COPD.

11. Global Strategy for Diagnosis, Management and Prevention of COPD n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations

12. Definition of COPD n COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. n Its pulmonary component is characterized by airflow limitation that is not fully reversible. n The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.

13. Classification of COPD Severity by Spirometry Stage I: Mild FEV 1 /FVC < 0.70 FEV 1 > 80% predicted Stage II: Moderate FEV 1 /FVC < 0.70 50% < FEV 1 < 80% predicted Stage III: Severe FEV 1 /FVC < 0.70 30% < FEV 1 < 50% predicted Stage IV: Very Severe FEV 1 /FVC < 0.70 FEV 1 < 30% predicted or FEV 1 < 50% predicted plus chronic respiratory failure

14. “At Risk” for COPD n COPD includes four stages of severity classified by spirometry. n A fifth category--Stage 0: At Risk--that appeared in the 2001 report is no longer included as a stage of COPD, as there is incomplete evidence that the individuals who meet the definition of “At Risk” (chronic cough and sputum production, normal spirometry) necessarily progress on to Stage I: Mild COPD. n The public health message is that chronic cough and sputum are not normal remains important - their presence should trigger a search for underlying cause(s).

15. Global Strategy for Diagnosis, Management and Prevention of COPD n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations

16. Burden of COPD: Key Points  COPD is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing.  COPD prevalence, morbidity, and mortality vary across countries and across different groups within countries.  The burden of COPD is projected to increase in the coming decades due to continued exposure to COPD risk factors and the changing age structure of the world’s population.

17. Burden of COPD: Prevalence  Many sources of variation can affect estimates of COPD prevalence, including e.g., sampling methods, response rates and quality of spirometry.  Data are emerging to provide evidence that prevalence of Stage I: Mild COPD and higher is appreciably higher in: - smokers and ex-smokers - people over 40 years of age - males

18. COPD Prevalence Study in Latin America The prevalence of post- bronchodilator FEV 1 /FVC < 0.70 increases steeply with age in 5 Latin American Cities Source: Menezes AM et al. Lancet 2005

19. Burden of COPD: Mortality  COPD is a leading cause of mortality worldwide and projected to increase in the next several decades.  COPD mortality trends generally track several decades behind smoking trends.  In the US and Canada, COPD mortality for both men and women have been increasing.  In the US in 2000, the number of COPD deaths was greater among women than men.

20. Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998 0 0 0.5 1.0 1.5 2.0 2.5 3.0 Proportion of 1965 Rate 1965 - 1998 –59% –64% –35% +163% –7% Coronary Heart Disease Coronary Heart Disease Stroke Other CVD COPD All Other Causes All Other Causes Source: NHLBI/NIH/DHHS

21. Of the six leading causes of death in the United States, only COPD has been increasing steadily since 1970 Source: Jemal A. et al. JAMA 2005

22. COPD Mortality by Gender, U.S., 1980-2000 Number Deaths x 1000 Source: US Centers for Disease Control and Prevention, 2002

23. Global Strategy for Diagnosis, Management and Prevention of COPD n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations

24. Risk Factors for COPD Lung growth and development Oxidative stress Gender Age Respiratory infections Socioeconomic status Nutrition Comorbidities Genes Exposure to particles ●Tobacco smoke ●Occupational dusts, organic and inorganic ●Indoor air pollution from heating and cooking with biomass in poorly ventilated dwellings ●Outdoor air pollution

25. Risk Factors for COPD Nutrition Infections Socio-economic status Aging Populations

26. Global Strategy for Diagnosis, Management and Prevention of COPD n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations

28. LUNG INFLAMMATION COPD PATHOLOGY Oxidativestress Proteinases Repairmechanisms Anti-proteinases Anti-oxidants Host factors Amplifying mechanisms Cigarette smoke Biomass particles Particulates Source: Peter J. Barnes, MD Pathogenesis of COPD

29. Alveolar wall destruction Loss of elasticity Destruction of pulmonary capillary bed ↑ Inflammatory cells macrophages, CD8 + lymphocytes Source: Peter J. Barnes, MD Changes in Lung Parenchyma in COPD

30. Chronic hypoxia Pulmonary vasoconstriction MuscularizationIntimalhyperplasiaFibrosisObliteration Pulmonary hypertension Cor pulmonale Death Edema Pulmonary Hypertension in COPD Source: Peter J. Barnes, MD

31. Y Y Y Mast cell CD4+ cell (Th2)Eosinophil Allergens Ep cells ASTHMA BronchoconstrictionAHR Alv macrophage Ep cells CD8+ cell (Tc1) Neutrophil Cigarette smoke Small airway narrowing Alveolar destruction COPD Reversible Irreversible Airflow Limitation Source: Peter J. Barnes, MD

32. Global Strategy for Diagnosis, Management and Prevention of COPD n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations

33. Four Components of COPD Management 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations

34. Relieve symptoms Prevent disease progression Improve exercise tolerance Improve health status Prevent and treat complications Prevent and treat exacerbations Reduce mortality GOALS of COPD MANAGEMENT VARYING EMPHASIS WITH DIFFERING SEVERITY

35. Four Components of COPD Management 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations

36. Management of Stable COPD Assess and Monitor COPD: Key Points  A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease.  The diagnosis should be confirmed by spirometry. A post-bronchodilator FEV 1 /FVC < 0.70 confirms the presence of airflow limitation that is not fully reversible.  Comorbidities are common in COPD and should be actively identified.

37. SYMPTOMS cough sputum shortness of breath EXPOSURE TO RISK FACTORS tobacco occupation indoor/outdoor pollution SPIROMETRY Diagnosis of COPD è è è è è è

38. Management of Stable COPD Assess and Monitor COPD: Spirometry  Spirometry should be performed after the administration of an adequate dose of a short- acting inhaled bronchodilator to minimize variability.  A post-bronchodilator FEV 1 /FVC < 0.70 confirms the presence of airflow limitation that is not fully reversible.  Where possible, values should be compared to age-related normal values to avoid overdiagnosis of COPD in the elderly.

39. Spirometry: Normal and Patients with COPD

40. Differential Diagnosis: COPD and Asthma COPD ASTHMA Onset in mid-life Symptoms slowly progressive Long smoking history Dyspnea during exercise Largely irreversible airflow limitation Onset early in life (often childhood) Symptoms vary from day to day Symptoms at night/early morning Allergy, rhinitis, and/or eczema also present Family history of asthma Largely reversible airflow limitation

41. COPD and Co-Morbidities COPD patients are at increased risk for: Myocardial infarction, angina Osteoporosis Respiratory infection Depression Diabetes Lung cancer COPD patients are at increased risk for: Myocardial infarction, angina Osteoporosis Respiratory infection Depression Diabetes Lung cancer

42. COPD and Co-Morbidities COPD has significant extrapulmonary (systemic) effects including: Weight loss Nutritional abnormalities Skeletal muscle dysfunction COPD has significant extrapulmonary (systemic) effects including: Weight loss Nutritional abnormalities Skeletal muscle dysfunction

43. Four Components of COPD Management 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations

44. Management of Stable COPD Reduce Risk Factors: Key Points  Reduction of total personal exposure to tobacco smoke, occupational dusts and chemicals, and indoor and outdoor air pollutants are important goals to prevent the onset and progression of COPD.  Smoking cessation is the single most effective — and cost effective — intervention in most people to reduce the risk of developing COPD and stop its progression (Evidence A).

45. Brief Strategies to Help the Patient Willing to Quit Smoking ASK Systematically identify all tobacco users at every visit. ADVISEStrongly urge all tobacco users to quit. ASSESS Determine willingness to make a quit attempt. ASSIST Aid the patient in quitting. ARRANGESchedule follow-up contact.

46. Management of Stable COPD Reduce Risk Factors: Smoking Cessation  Counseling delivered by physicians and other health professionals significantly increases quit rates over self-initiated strategies. Even a brief (3-minute) period of counseling to urge a smoker to quit results in smoking cessation rates of 5-10%.  Numerous effective pharmacotherapies for smoking cessation are available and pharmacotherapy is recommended when counseling is not sufficient to help patients quit smoking.

47. Management of Stable COPD Reduce Risk Factors: Indoor/Outdoor Air Pollution  Reducing the risk from indoor and outdoor air pollution is feasible and requires a combination of public policy and protective steps taken by individual patients.  Reduction of exposure to smoke from biomass fuel, particularly among women and children, is a crucial goal to reduce the prevalence of COPD worldwide.

48. Four Components of COPD Management 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations

49. Management of Stable COPD Manage Stable COPD: Key Points  The overall approach to managing stable COPD should be individualized to address symptoms and improve quality of life.  For patients with COPD, health education plays an important role in smoking cessation (Evidence A) and can also play a role in improving skills, ability to cope with illness and health status.  None of the existing medications for COPD have been shown to modify the long-term decline in lung function that is the hallmark of this disease (Evidence A). Therefore, pharmacotherapy for COPD is used to decrease symptoms and/or complications.

50. Management of Stable COPD Pharmacotherapy: Bronchodilators  Bronchodilator medications are central to the symptomatic management of COPD (Evidence A). They are given on an as-needed basis or on a regular basis to prevent or reduce symptoms and exacerbations.  The principal bronchodilator treatments are ß 2 -agonists, anticholinergics, and methylxanthines used singly or in combination (Evidence A).  Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators (Evidence A).

51. Management of Stable COPD Pharmacotherapy: Glucocorticosteroids  The addition of regular treatment with inhaled glucocorticosteroids to bronchodilator treatment is appropriate for symptomatic COPD patients with an FEV1 < 50% predicted (Stage III: Severe COPD and Stage IV: Very Severe COPD) and repeated exacerbations (Evidence A).  An inhaled glucocorticosteroid combined with a long-acting ß 2 -agonist is more effective than the individual components (Evidence A).

52. Management of Stable COPD Pharmacotherapy: Glucocorticosteroids  The dose-response relationships and long- term safety of inhaled glucocorticosteroids in COPD are not known.  Chronic treatment with systemic glucocorticosteroids should be avoided because of an unfavorable benefit-to-risk ratio (Evidence A).

53. Management of Stable COPD Pharmacotherapy: Vaccines  In COPD patients influenza vaccines can reduce serious illness (Evidence A).  Pneumococcal polysaccharide vaccine is recommended for COPD patients 65 years and older and for COPD patients younger than age 65 with an FEV 1 < 40% predicted (Evidence B).

54. Management of Stable COPD All Stages of Disease Severity n Avoidance of risk factors - smoking cessation - reduction of indoor pollution - reduction of occupational exposure n Influenza vaccination n Avoidance of risk factors - smoking cessation - reduction of indoor pollution - reduction of occupational exposure n Influenza vaccination

55. IV: Very Severe III: Severe II: Moderate I: Mild Therapy at Each Stage of COPD  FEV 1 /FVC < 70%  FEV 1 > 80% predicted  FEV 1 /FVC < 70%  50% < FEV 1 < 80% predicted  FEV 1 /FVC < 70%  30% < FEV 1 < 50% predicted  FEV 1 /FVC < 70%  FEV 1 < 30% predicted or FEV 1 < 50% predicted plus chronic respiratory failure Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add long term oxygen if chronic respiratory failure. Consider surgical treatments

56. Management of Stable COPD Other Pharmacologic Treatments  Antibiotics: Only used to treat infectious exacerbations of COPD  Antioxidant agents: No effect of n- acetylcysteine on frequency of exacerbations, except in patients not treated with inhaled glucocorticosteroids  Mucolytic agents, Antitussives, Vasodilators: Not recommended in stable COPD

57. Management of Stable COPD Non-Pharmacologic Treatments  Rehabilitation: All COPD patients benefit from exercise training programs, improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue (Evidence A).  Oxygen Therapy: The long-term administration of oxygen (> 15 hours per day) to patients with chronic respiratory failure has been shown to increase survival (Evidence A).

58. Four Components of COPD Management 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations 1.Assess and monitor disease 2.Reduce risk factors 3.Manage stable COPD l Education l Pharmacologic l Non-pharmacologic 4.Manage exacerbations Revised 2006

59. Management COPD Exacerbations Key Points An exacerbation of COPD is defined as: “An event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.”

60. Management COPD Exacerbations Key Points  The most common causes of an exacerbation are infection of the tracheobronchial tree and air pollution, but the cause of about one-third of severe exacerbations cannot be identified (Evidence B).  Patients experiencing COPD exacerbations with clinical signs of airway infection (e.g., increased sputum purulence) may benefit from antibiotic treatment (Evidence B).

61. Manage COPD Exacerbations Key Points  Inhaled bronchodilators (particularly inhaled ß 2 -agonists with or without anticholinergics) and oral glucocortico- steroids are effective treatments for exacerbations of COPD (Evidence A).

62. Management COPD Exacerbations Key Points  Noninvasive mechanical ventilation in exacerbations improves respiratory acidosis, increases pH, decreases the need for endotracheal intubation, and reduces PaCO 2, respiratory rate, severity of breathlessness, the length of hospital stay, and mortality (Evidence A).  Medications and education to help prevent future exacerbations should be considered as part of follow-up, as exacerbations affect the quality of life and prognosis of patients with COPD.

63. Global Strategy for Diagnosis, Management and Prevention of COPD n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations

64. Translating COPD Guidelines into Primary Care KEY POINTS n Better dissemination of COPD guidelines and their effective implementation in a variety of health care settings is urgently required. n In many countries, primary care practitioners treat the vast majority of patients with COPD and may be actively involved in public health campaigns and in bringing messages about reducing exposure to risk factors to both patients and the public. n Better dissemination of COPD guidelines and their effective implementation in a variety of health care settings is urgently required. n In many countries, primary care practitioners treat the vast majority of patients with COPD and may be actively involved in public health campaigns and in bringing messages about reducing exposure to risk factors to both patients and the public.

65. Translating COPD Guidelines into Primary Care KEY POINTS n Spirometric confirmation is a key component of the diagnosis of COPD and primary care practitioners should have access to high quality spirometry. n Older patients frequently have multiple chronic health conditions. Comorbidities can magnify the impact of COPD on a patient’s health status, and can complicate the management of COPD. n Spirometric confirmation is a key component of the diagnosis of COPD and primary care practitioners should have access to high quality spirometry. n Older patients frequently have multiple chronic health conditions. Comorbidities can magnify the impact of COPD on a patient’s health status, and can complicate the management of COPD.

66. Global Strategy for Diagnosis, Management and Prevention of COPD SUMMARY n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations

67. Global Strategy for Diagnosis, Management and Prevention of COPD: Summary  COPD is increasing in prevalence in many countries of the world.  COPD is treatable and preventable.  The GOLD program offers a strategy to identify patients and to treat them according to the best medications available.

68.  COPD can be prevented by avoidance of risk factors, the most notable being tobacco smoke.  Patients with COPD have multiple other conditions (comorbidities) that must be taken into consideration.  GOLD has developed a global network to raise awareness of COPD and disseminate information on diagnosis and treatment. Global Strategy for Diagnosis, Management and Prevention of COPD: Summary

69. United States United Kingdom Argentina Australia Brazil Austria Canada Chile Belgium China Denmark Columbia Croatia Egypt Germany Greece Ireland Italy Syria Hong Kong ROC Japan Iceland India Korea Kyrgyzstan Uruguay Moldova Nepal Macedonia Malta Netherlands New Zealand Poland Norway Portugal Georgia Romania Russia Singapore Slovakia Slovenia Saudi Arabia South Africa Spain Sweden Thailand Switzerland Ukraine United Arab Emirates Taiwan ROC Venezuela Vietnam Peru Yugoslavia Albania Bangladesh France Mexico Turkey Czech Republic Pakistan Israel GOLD National Leaders Philippines

70. WORLD COPD DAY November 14, 2007 WORLD COPD DAY November 14, 2007 Raising COPD Awareness Worldwide

71. GOLD Website Address http://www.goldcopd.org

72. ADDITIONAL SLIDES WITH NOTES PREPARED BY: PROFESSOR PETER J. BARNES, MD NATIONAL HEART AND LUNG INSTITUTE LONDON, ENGLAND

73. Mucus gland hyperplasia Goblet cell hyperplasia Mucus hypersecretion Neutrophils in sputum Squamous metaplasia of epithelium ↑ Macrophages No basement membrane thickening Little increase in airway smooth muscle ↑ CD8 + lymphocytes Changes in Large Airways of COPD Patients Source: Peter J. Barnes, MD

74. Disrupted alveolar attachments Inflammatory exudate in lumen Peribronchial fibrosis Lymphoid follicle Thickened wall with inflammatory cells - macrophages, CD8 + cells, fibroblasts Changes in Small Airways in COPD Patients Source: Peter J. Barnes, MD

75. Alveolar wall destruction Loss of elasticity Destruction of pulmonary capillary bed ↑ Inflammatory cells macrophages, CD8 + lymphocytes Changes in the Lung Parenchyma in COPD Patients Source: Peter J. Barnes, MD

76. Endothelial dysfunction Intimal hyperplasia Smooth muscle hyperplasia ↑ Inflammatory cells (macrophages, CD8 + lymphocytes) Changes in Pulmonary Arteries in COPD Patients Source: Peter J. Barnes, MD

77. LUNG INFLAMMATION COPD PATHOLOGY Oxidativestress Proteinases Repairmechanisms Anti-proteinases Anti-oxidants Host factors Amplifying mechanisms Cigarette smoke Biomass particles Particulates Pathogenesis of COPD Source: Peter J. Barnes, MD

78. Cigarette smoke (and other irritants) PROTEASES PROTEASES Neutrophil elastase CathepsinsMMPs Alveolar wall destruction (Emphysema) Mucus hypersecretion CD8 + lymphocyte Alveolar macrophage Epithelialcells Fibrosis Fibrosis(Obstructivebronchiolitis) Fibroblast MonocyteNeutrophil Chemotactic factors Inflammatory Cells Involved in COPD Source: Peter J. Barnes, MD

79. Anti-proteases SLPI  1 -AT Proteolysis O 2 -, H 2 0 2 OH., ONOO -  Mucus secretion Plasma leak Bronchoconstriction NF-  B IL-8 Neutrophil recruitment TNF-  Isoprostanes ↓ HDAC2 ↑InflammationSteroidresistance MacrophageNeutrophil Oxidative Stress in COPD Source: Peter J. Barnes, MD

80. Differences in Inflammation and its Consequences: Asthma and COPD Y Y Y Mast cell CD4+ cell (Th2)Eosinophil Allergens Ep cells ASTHMA BronchoconstrictionAHR Alv macrophage Ep cells CD8+ cell (Tc1) Neutrophil Cigarette smoke Small airway narrowing Alveolar destruction COPD Reversible Irreversible Airflow Limitation Source: Peter J. Barnes, MD

81. Normal Inspiration Expiration alveolar attachments Mild/moderate COPD loss of elasticity Severe COPD loss of alveolar attachments closure smallairway Dyspnea ↓ Exercise capacity Air trapping Hyperinflation ↓ Health status Air Trapping in COPD Source: Peter J. Barnes, MD

82. Chronic hypoxia Pulmonary vasoconstriction MuscularizationIntimalhyperplasiaFibrosisObliteration Pulmonary hypertension Cor pulmonale Death Edema Pulmonary Hypertension in COPD Source: Peter J. Barnes, MD

83. Macrophages TNF-  IL-8 IL-6 Bacteria Viruses Non-infective Pollutants Epithelial cells Oxidative stress Neutrophils Inflammation in COPD Exacerbations Source: Peter J. Barnes, MD