Pathophysiology of asthma and chronic obstructive pulmonary disease M. Tatár

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

End of quiet expiration - 0.5 - 2.5 0.5 Inspiration

Inspiration - 2.5 + 2.0 Forced expiration 0.5 - 2.0 - 1.5 - 1.0 - 0.5

Forced expiration + 2.0 0.5 + 2.5 + 2.0 + 1.5 + 1.0 EPP

Bronchial asthma

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

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

Classification A. Allergic asthma atopy, genetic predisposition  IgE, mast cells and eosinophils response to allergens A. Nonallergic asthma no environmental causes can be identified negative skin test to common airborn allergens rather negative family history C. Occupational asthma sensibilisation of airways to inhalant chemicals

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

Triggers – mechanisms of action Respiratory infections epithelial damage airway inflammation Exercise hyperventilation (reflex airflow limitation) - cooling of mucosa - osmolarity changes of fluid lining epithelium Emotions (laughing, crying, anger, fear) hyperventilation hypocapnia (bronchioloconstriction)

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

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

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

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

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) - mast cells, eosinophils

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

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

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

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

Chronic obstructive pulmonary disease (COPD)

Definition Disease characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to inhaled noxious particles or gases. Chronic expiratory flow limitation -  maximum expiratory flows - slow forced emptying of the lungs Combination of two pathological processes - airways damage - emphysema

COPD Chronic bronchitis Emphysema 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

Chronic airflow limitation - mechanisms Chronic inflammation causes: - structural changes and narrowing of the small airways (obstructive bronchiolitis) - destruction of the lung parenchyma leads to the loss of alveolar attachments to the small airways and decreasing lung elastic recoil - these changes diminish the ability of the airways to remain open during expiration

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

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

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

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

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

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

COPD phenotypes symptoms obstruction severity risk of exacerbations occurrence of comorbidities

Frequent comorbidities Loss of weight Dysfunction of skeletal muscles Osteoporosis Progression of aterosclerosis and coronary artery disease

Systemic inflammation

Local and systemic inflammation