1. Pulmonary Pathophysiology III Iain MacLeod, Ph.D imacleod@hsph.harvard.edu Iain MacLeod 16 November 2009

2. Review – Pulmonary II - Obstruction Should be a well-understood concept that when an airway narrows its resistance greatly increases Airway resistance, and thus obstruction, can be easily measured by determining the FEV 1 / FVC ratio. The FVC is measured by having a person take in as much air as they possibly can and then breathe out as much as they can into a spirometer, until no more air will come out. The total amount of air that they breathe out is the FVC. The FEV 1 is the amount of air that comes out in the first second. The technique has the advantage of being mostly effort independent. A value less than 80% indicates that an airway obstruction may be present

3. Review – Pulmonary II - Asthma

4. FEV 1 /FVC is greatly reduced during an attack – why ?

5. Review – Pulmonary II - Asthma FEV 1 /FVC is greatly reduced during an attack – why ? Bronchoconstriction - Airway hyperresponsiveness: increased airway narrowing in response to contractile agonists that have little if any effect in normal subjects histamine, methacholine, leukotrienes – can be diagnostic using the PD 20

6. Review – Pulmonary II - Asthma FEV 1 /FVC is greatly reduced during an attack – why ? Bronchoconstriction - Airway hyperresponsiveness: increased airway narrowing in response to contractile agonists that have little if any effect in normal subjects histamine, methacholine, leukotrienes – can be diagnostic using the PD 20 Inflammation - Mediated mainly by lymphocytes (CD4 and CD8 T cells) and eosinophils. IL-5 Granules IgE Diffusion & Contraction Allergy

7. Review – Pulmonary II – Asthma & Allergy IgE – important in inducing an inflammatory state in response to allergens. Like all antibodies, IgE is produced by B cells, which in turn are stimulated by T cells One region of the IgE molecule will bind to mast cells, while another region will recognize a specific allergen. This causes mast cells to degranulate rapidly – contain preformed inflammatory mediators such as histamine. Strong correlation between IgE titer and asthma severity Biphasic response to allergens – immediate and late (why?)

8. Review – Pulmonary II – Asthma Treatment What do each of these do ? Corticosteroids  -agonists Leukotriene Synthesis Inhibitors Omalizumab

9. Review – Pulmonary II – Asthma - Influencing Factors Nature vs. Nurture - genetic factors involved in IgE synthesis - exposure to viruses / allergens / cigarette smoke Why is asthma on the increase? - hygiene hypothesis - obesity - allergens - pollution

10. Review – Pulmonary II - COPD Emphysema and Chronic Bronchitis

11. Review – Pulmonary II - COPD Emphysema and Chronic Bronchitis destruction of alveolar wall and capillary bed but without obvious scarring (fibrosis). enlarged air spaces small airways are narrowed, thin walled, may be reduced in number pan acinar - central part of acinus (respiratory bronchioles mainly affected) pan lobular ‑ whole acinus afflicted apex of lung most often affected first increased pulmonary compliance (elastase) hypertrophy of mucus glands goblet cell metaplasia inflammation in small airways and in glands mucus in airways, sometimes occluding airway lumen airway wall edema thickened epithelium

12. Review – Pulmonary II – COPD - Emphysema Inhaled toxins trigger local inflammation in alveoli Inflammatory mediators cause the destruction of alveolar septum – decrease in surface area available for gas exchange Additional destruction of capillaries that serve alveoli. Ventilation/ Perfusion inequality – some areas of the lung could receive large quantities of air but have insufficient blood flow (or vice versa). Lower PaO 2 but normal PaCO 2 (although PaCO 2 will rise once disease becomes extensive)

13. Review – Pulmonary II – COPD - Emphysema How does emphysema lead to pulmonary hypertension ? - as disease progresses and high enough PaO 2 cannot be reached, the body compensates through vasoconstriction. - the heart tries to provide more blood to the lungs in order for PaO 2 to increase, leading to thickening of the heart muscle. Eventual heart failure ensues. What role does  1 anti-trypsin play? (Discuss)