Pathophysiology of asthma and chronic obstructive pulmonary disease

1. Pathophysiology of asthmaand chronic obstructive pulmonary disease M. Tatár

3. OBSTRUCTIVE LUNG DISEASES localized: laryngeal constriction, tracheal and bronchial carcinoma, foreign bodies generalized: asthma, COPD, bronchiectasis, cystic fibrosis OBSTRUCTIVE VENTILATORY DISORDER - spirometry Airflow limitation

5. End of quiet expiration - 0.5 - 2.5 0.5 Inspiration 0 0 0 0 0

6. Inspiration - 2.5 + 2.0 Forced expiration 0.5 - 2.0 - 1.5 - 1.0 - 0.5 0

7. Forced expiration + 2.0 0.5 + 2.5 + 1.0 0 + 2.0 + 1.5 EPP

8. ASTHMA - definition Chronic inflammatory disorder of the airways Mast cells, eosinophils, T-lymphocytes Recurrent episodes of wheezing, dyspnoea, and cough particularly at night and early morning Symptoms are associated with airflow limitation that is partly reversible either spontaneously or with therapy Bronchial hyperresponsiveness is present very often

9. Volume Normal subject Asthmatic (after bronchodilator) Asthmatic (before bronchodilator) FEV1 1 2 3 4 5 Time (seconds)

10. ASTHMA - classification A. Intrinsic asthma • no environmental causes can be identified • negative skin test to common airborn allergens • rather negative family history B. Extrinsic asthma • atopy, genetic predisposition •  IgE, mast cells and eosinophils response to allergens C. Occupational asthma • sensibilisation of airways to inhalant chemicals

11. Development of asthma Risk factors Predisposing: atopy, gender Causal: allergens, aspirin, chemicals Contributing: respiratory infections, diet, air pollution, smoking Factors that exacerbate asthma - triggers allergens, respiratory infections, exercise, emotions

12. Triggers Respiratory infections • epithelial damage • airway inflammation Exercise  reflex airflow limitation • cooling of mucosa • osmolarity changes of fluid lining epithelium Emotions (laughing, crying, anger, fear) • hyperventilation • hypocapnia

13. Asthma - bronchial hyperresponsiveness Instability of the airways = exaggerated bronchoconstrictor response to a wide variety of stimuli Key factor - airway inflammation Mechanisms: direct and indirect

14. Airway hyperresponsiveness Direct agonists e.g. methacholine Nerve Airway with limited airflow Mediators SO2, bradykinin Indirect agonists e.g. exercise, adenosine, hypotonic or hypertonic aerosols Mast cell

15. antihyperreactiv factors prohyperreactiv factors 2-adrenergic  -adrenergic  VIP/PHM  cholinergic  anticholinergic  im balance  SP/NK NEP  oxygen-free radicals  antioxidants  peptidases  corticoids Airway hyperresponsiveness Normal airway reactivity

16. Pathological changes in chronic asthma Airway wall remodeling Normal airway Epithelium Basement membrane Smooth muscle Mucus plug Mucus glands

17. Mechanisms of asthma 1. Airway inflammation - recruitments of inflammatory cells from circulation - endothelial adhesion molecules - activation of T lymphocytes (Th2 clone) -  production of IgE, leukotriens, prostanoids - cytokines (CD4+ Th subtype) 2. Neural control of airways

19. Neurogenic inflammation Antigen etc. Macrophage Mast cell T-lymphocyte Neutrophil Eosinophil Mucus plug Epithelial shedding Vasodilation Subepithelial fibrosis Sensory nerve Plasma leak Efferent nerve Oedema Airway constriction and smooth muscle hypertrophy/hyperplasia

20. Asthma - airflow limitation 1. Acute bronchoconstriction 2. Swelling of the airway wall 3. Chronic mucus plug formation 4. Airway wall remodeling

21. Relaxation Constriction muscle constriction 35 % Airway narrowing Normal R = 10 R = 1 muscle constriction 35 % Exaggerated airway narrowing Asthma R = 2 R = 40

22. INFLAMMATION Risk factors (for development of asthma) Airway hyperresponsiveness Airflow limitation Symptoms Risk factors (for exacerbations)

23. Asthma is a highly variable disease Asthma is a chronic inflammatory disease of variable severity. Worsening and exacerbations of asthma are associated with episodes of acute inflammation, which develop on top of persistent underlying chronic inflammation. This acute inflammation causes an increase in symptoms and may also lead to an increased sensitivity to triggers and a worsening in airway hyperresponsiveness. The variability and severity of „real life“ asthma is dependent on a number of factors, including a patient´s adherence to the prescribed treatment.

26. COPD - definition Chronic airflow limitation (  maximum expiratory flow, slow forced emptying of the lungs) Airflow limitation is slowly progressive and irreversible • Due to varying combinations of: • airway disease • emphysema

27. Chronic bronchitis defined in clinical terms chronic cough with sputum production - (3 months a year, 2 successive years) - excluded cardiac or other pulmonary causes Emphysema defined anatomically permanent, destructive enlagrement of airspaces distal to the terminal bronchioles without obvious fibrosis COPD

31. COPD - risk factors Cigarette smoking 1 - antitrypsin deficiency Solid fuel used for indoor heating or cooking without adequate ventilation Heavily polluted environments

32. 100 Never smoked 75 Smoked regularly Stopped at age 45 yrs FEV1 % 50 Disability 25 Stopped at age 65 yrs Death 0 75 25 50 Age yrs

33. COPD - cellular and biochemical mechanisms Inflammation: alveolar macrophages, neutrophils  production of elastase, cathepsine G, collagenase  oxidative stress in smokers and in COPD patients Neutrophil and macrophage enzymes and oxidants destroy components of extracellular matrix (collagen, elastin, fibronectine, proteoglycans) Loss of cellular components of lung parenchyma: - elastase can induce apoptosis - cells exposed to oxidants may undergo apoptosis or necrosis

34. COPD - cellular and biochemical mechanisms Imbalance proteases antiproteases system oxidants antioxidants Destruction of lung parenchyma Small airways disorder

40. COPD - pathology of peripheral airways • mucus plugging • goblet cell metaplasia • fibrosis • smooth muscle hypertrophy

42. 12 Maximal expiratory effort 6 V´ ( l.s-1 ) 0 Spontaneous breath - 6 0 1 2 3 4 5 Volume from TLC ( l )

43. 100 IRV IRV VT Airflow limit 80 Lung volume (% TLC) VT Normals 60 40 20 40 0 Oxygen consumption (ml.min-1.kg-1)

45. Emphysema Relatively normal lung region, normal PAO2 Airway narrowing Emphysematous region  PAO2 Destruction of capillary  V´  V´  CaO2 Relatively normal CaO2  Q´   Q´ Pulm. artery Pulm. vein Normal CaO2 ´

47. Bronchitis Airway narrowing Relatively normal lung region, normal PAO2  PAO2 normal CaO2 norm V´  V´  CaO2  CaO2 normQ´ norm Q´ Pulm. a. Pulm. v.

48. 10 PaCO2 ( kPa ) 6 4 0 0,5 1,0 1,5 2,0 2,5 3,0 FEV1 ( l )

49. 100 80 60 Oxygen saturation ( % ) 40 20 REM REM REM Sleep period

50. Components of chronic obstructive pulmonary disease Emphysema but no COPD Emphysema Chronic bronchitis Simple bronchitis Airflow limitation by spirometry Asthma Asthma with no airflow limitation