1. Obstructive Airway Diseases Chronic (Obstructive) Bronchitis Emphysema Bronchiectasis Asthma

2. Permanent bronchial dilation associated with suppuration (pus production) Occurs commonly with cystic fibrosis Results from infection and scarring (fibrous tissue formation) Bronchi are dilated, due to ‘contraction’ effect of fibrous tissue but can be fibrous obstruction leading to distal mucous retention and superimposed bacterial infection Bronchi become filled with mucous and neutrophils, producing copious, foul smelling sputum Secondary inflammation  further destruction of airways and alveolar walls fibrosis of lung parenchyma Bronchiectasis

3. Defined as increased irritability of the bronchial tree with paroxysmal airway narrowing Accounts for more paediatric hospital admissions in UK than any other single cause Two broad categories:- Extrinsic (Allergic) Intrinsic (Non-allergic) Two types may co-exist Asthma

4. Basis of intrinsic asthma is unknown precipitated by non-allergenic factors eg inhaled irritants, infection, stress, cold air, exercise Basis of extrinsic asthma is immunologic typically precipitated by type 1 (IgE-mediated) hypersensitivity reactions to inhaled allergens immediate but type 3 reactions may also be involved in some cases triggered by soluble antigen/antibody immune complexes deposited in tissues Variable presentation, from slight wheezing to severe dyspnoea Asthma

5. Pathophysiology involves 3 main mechanisms:- Reversible bronchoconstriction Thickening of the bronchial mucosa due to oedema and infiltration of inflammatory cells Mucous plugging of the bronchiolar lumen Allergic asthma has 2 phases ‘early phase’ (occurring within minutes) ‘late phase’ (occurring at 2-8 hours) Asthma

6. Early phase result of:- Original antigen exposure primes B lymphocytes Consequent production of specific IgE IgE binding to mast cells, eosinophils, macrophages and platelets Release of inflammatory mediators, including histamine, various leukotrienes (LTB4, LTC4, LTD4, etc.) and prostanoids. Processes occur within minutes Hence known as the ‘early phase’ of an asthma attack Allergic Asthma: Early Phase

7. Late phase consists of:- Further release of inflammatory cytokines, including GM-CSF (Granulocyte Macrophage Colony- Stimulating Factor), IL4, IL5, TNF, etc. These act as chemoattractants for eosinophils, neutrophils and other inflammatory cells These, in turn, release leukotrienes, platelet activating factor (PAF), proteases, major basic protein (MBP), eosinophilic cation protein, etc. These result in increased inflammation and oedema, mucous secretion, vasodilatation, bronchoconstriction and damage to the bronchial epithelium Allergic Asthma: Late Phase

8. Bronchial hypersensitivity may involve… Increased mucosal inflammation due to increased numbers of eosinophils? Increased activity of irritant receptors and axon reflexes  release of bronchoconstrictor neuropeptides such as substance P ? Increased vagal stimulation and decreased adrenergic stimulation of bronchial smooth muscle  bronchoconstriction and increased mediator release Increased Ca 2+ influx into smooth muscle  increased bronchoconstriction into mast cells  degranulation Non-Allergic Asthma

9. If possible treat the cause… For COPD, this invariably means reducing exposure to noxious agents to limit (irreversible) damage Reduce atmospheric pollution Stop smoking! Treat concurrent infections/allergies It may be necessary, either additionally or alternatively, to treat the effects Treatment of Obstructive Disorders

10. Treatment of cause may include:- Antibiotics for infectious bacterial causes, or as prophylaxis against secondary bacterial infections in viral and other infections Anti-allergic therapies in immune-induced disorders Removal of physical obstructions Treatment of effect may include:- Bronchodilator agents Anti-inflammatory agents Others Treatment of Obstructive Disorders

11. β 2 -adrenoceptor agonists Act primarily on bronchial smooth muscle β 2 -adrenoceptors to increase intracellular cAMP Additionally they may:- Prevent mast cell degranulation Decrease microvascular permeability, and hence oedema Increase mucociliary transport Primarily of short-term use since prolonged use can lead to receptor down-regulation and reduced efficacy which may be reversed with steroids Main agents are salbutamol, terbutaline, (short acting, inhaled) salmeterol, eformoterol (long acting, used for prophylaxis) Bronchodilator Agents

12. Muscarinic ACh antagonists Ipratropium, oxitropium are examples Administered by inhalation Usually less effective bronchodilators than β 2 -adrenoceptor agonists Methylxanthines Phosphodiesterase inhibitors  increase cAMP by reducing breakdown Now usually only used as second line drugs Not as specific as β 2 -agonists Examples include theophylline and aminophylline Bronchodilator Agents

13. Glucocorticoids No direct effect on bronchial calibre Thought to work via inhibition of synthesis and release of prostanoids, leukotrienes and cytokines as well as on eosinophils Also up-regulate β-receptors Hydrocortisone (IV) and prednisolone (oral) are used for management of status asthmaticus Progressive, unresponsive, severe asthma Beclomethasone, Fluticasone, Budesonide, etc (inhalation) for more general use Anti-inflammatory agents

14. Lipoxygenase inhibitors Inhibits activity of 5-lipoxygenase Main enzyme for synthesis of leukotrienes, eg LTB4, LTC4 and LTD4 New group; first FDA-approved example was Zileuton Others Sodium chromoglycate and nedocromil sodium inhibit both early and late phases of asthma Mode of action is unclear, but may involve inhibition of mediator release from inflammatory cells, suppression of axon reflexes inhibition of action of Platelet Activating Factor (PAF) Anti-inflammatory agents

15. Leukotriene receptor antagonists block LTD4 receptors inhibit inflammation, mucosal oedema and bronchoconstriction Eg zafirlukast, montelukast Histamine receptor antagonists block H1 receptors inhibit IgE-mediated neutrophil influx and PAF-mediated eosinophil influx Eg terfenadine, astemizole, azelastine Ca 2+ channel antagonists reduce Ca 2+ -dependent release of mucous and chemical mediators Eg nifedipine, verapamil Others Agents

16. K + channel openers hyperpolarises bronchial smooth muscle  bronchodilation Eg cromakalim Antibodies prevent the binding of IgE to mast cells Eg IgE MCAs Nitric oxide (NO) donors/PAF antagonists none yet available NO as inflammatory marker NO sensor as early warning for asthmatics? Others Agents

17. Summary

18. Already looked at Obstructive Compromised airflow Eg reduced FEV 1 Now briefly look at Restrictive Reduced capacity Eg reduced FVC Restrictive Lung Disease

19. Causes - infection/sepsis/trauma/O 2 toxicity Risk Groups - Adults Pathophysiology Initiated by damage to alveolar endothelium & Type II pneumocytes Impaired gas exchange due to pulmonary hemorrhage, pulmonary oedema, or atelectasis Complement activation, sepsis Features Acute dyspnea, respiratory failure Hypoxia (cyanosis) Heavy, wet lungs Acute Respiratory Distress Syndrome (ARDS)

20. Causes - Unknown Risk Groups – females, young, black Pathophysiology Small lumps (granulomas) due to chronic inflammation Multi-system (eg lungs, lymph nodes, eyes, joints etc) Features Dyspnea on exertion Dry cough, fever, fatigue Uveitis, dry eyes Polyarthritis Sarcoidosis

21. Causes – Exposure to organic antigens Risk Groups – Occupational (farms, birds, etc) Pathophysiology Type III & IV hypersensitivity reactions Chronic interstitial inflammation Alveolar damage  fibrotic lung Features Acute or chronic Dry cough Chest tightness General malaise, fever Hypersensitivity Pneumonitis (Farmer’s Lung)

22. Causes – Unknown Risk Groups – Male, 50-60 y, smoking Pathophysiology Chronic inflammation of alveolar wall  fibrosis Usually fatal within 4-6 years Features Velcro-like rales Honeycomb lung (end stage) Finger-clubbing due to disorder in megakaryocyte fragmentation in lungs  aggregation in small vessels at finger tips? Idiopathic Pulmonary Fibrosis