Pathophysiology of asthma and chronic obstructive pulmonary disease

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

3. OBSTRUCTIVE LUNG DISEASES localized: laryngealconstriction, tracheal and bronchialcarcinoma, foreignbodies 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. Bronchial asthma

9. ASTHMA - definition Heterogeneous, multifactorial disease with variable and mostly reversible respiratory pathway obstruction based on a chronic bronchial inflammatory reaction. Symptoms (wheezing, cough particularly at night and early morning, dyspnoea – chest tightness or shortness of breath) are variable and correlated with expiratory flow limitation. Bronchial hyperresponsiveness is often present

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

11. Classification A. Allergicasthma • atopy, geneticpredisposition •  IgE, mastcells and eosinophilsresponse to allergens A. Nonallergicasthma • no environmentalcausescanbeidentified • negative skin test to commonairbornallergens • rathernegativefamilyhistory C. Occupationalasthma • sensibilisation of airways to inhalantchemicals

12. 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

13. Triggers – mechanisms of action Respiratoryinfections • epithelialdamage • airwayinflammation Exercise • hyperventilation (reflex airflowlimitation) - cooling of mucosa - osmolaritychanges of fluid liningepithelium Emotions (laughing, crying, anger, fear) • hyperventilation • hypocapnia (bronchioloconstriction)

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

15. Airway hyperresponsiveness Direct antagonists (methacholine) Nerve Airway with limited airflow SO2, bradykinin Mediators Indirect agonists (exercise, hypotonic or hypertonic aerosols Mast cell

16. antihyperreactivefactors prohyperreactive factors 2-adrenergic -adrenergic VIP/PHM cholinergic anticholinergic SP/NK neutral peptidases free radicals antioxidants peptidases (Neu) corticoids

17. Pathological changes in airways asthma normal epithelium basement membrane smooth muscle mucus plug mucus glands

18. Mechanisms of asthma 1. Airway inflammation - recruitments of inflammatorycellsfromcirculation - endothelialadhesionmolecules - activation of T lymphocytes (Th2 clone) -  production of IgE, leukotriens, prostanoids - cytokines (CD4+ Th subtype) - mastcells, eosinophils

19. Neural control of airways - 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. Mechanisms of expiratory flow limitation 1. Acute bronchoconstriction 2. Swelling of theairwaywall - vasodilation - infiltration (Eo, Neu) 3. Chronic mucus plug formation 4. Airway wall remodeling

21. Bronchoconstriction  airflow resistance muscle constriction 35 % Normal R = 10 R = 1 muscle constriction 35 % Asthma R = 2 R = 40

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

25. Chronic obstructive pulmonary disease (COPD)

26. Definition Diseasecharacterized by persistentairflowlimitationthatis usuallyprogressive and associatedwithanenhancedchronic inflammatoryresponse in theairways and thelung to inhaled noxiousparticles or gases. Chronic expiratory flow limitation -  maximum expiratory flows - slow forced emptying of the lungs Combination of two pathological processes - airways damage - 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 definedanatomically permanent, destructiveenlagrement of airspacesdistal to theterminalbronchioleswithoutobviousfibrosis COPD

28. Chronic airflow limitation - mechanisms Chronicinflammationcauses: - structuralchanges and narrowing of thesmallairways (obstructivebronchiolitis) - destruction of thelungparenchymaleads to theloss of alveolarattachments to thesmallairways and decreasinglungelasticrecoil - thesechangesdiminishtheability of theairways to remainopenduringexpiration

31. Risk factors Cigarette smoking 1 - antitrypsindeficiency Solid fuel used for indoor heating or cooking without adequate ventilation Heavilypollutedenvironments

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. Cellular and biochemical mechanisms Inflammation: alveolar macrophages, CD8+ T lymphocytes, 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 necrosis

34. Imbalance proteases antiproteases system oxidants antioxidants Small airways disorder Destruction of lung parenchyma

39. Pathology of peripheral airways • mucus plugging • goblet cell hyper/metaplasia • fibrosis • smooth muscle hypertrophy

40. Peak exp. flow Maximal expiratory efforts 12 6 V´ ( l.s-1 ) 0 - 6 25 50 75 100 0 VC ( % exhaled)

41. COPD phenotypes symptoms obstruction severity risk of exacerbations occurrence of comorbidities

42. Frequentcomorbidities Loss of weight Dysfunction of skeletal muscles Osteoporosis Progression of aterosclerosis and coronary artery disease

43. Systemic inflammation

44. Local and systemicinflammation