Obstructive Airway Diseases

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

2. Chronic Bronchitis & Emphysema • Almost always co-exist • Together known as Chronic Obstructive Pulmonary Disease (COPD) • or Chronic Obstructive Airway Disease (COAD) • Affects 6% of men and 4% of women over 45 in UK • Chronic bronchitis is • chronic productive cough for 3 mo per year over 2 years • Emphysema is • permanent enlargement of the airspaces distal to terminal bronchioles • alveolar wall destruction

3. COPD: Definition • A disease state characterised by airflow limitation that is not fully reversible • Airflow limitation is usually both • progressive and • associated with abnormal inflammatory response of lungs to noxious particles or gases • primary cause is tobacco smoke

4. COPD: Facts • COPD is the 4th leading cause of death in the United States (behind heart disease, cancer, and cerebrovascular disease) • In 2005, the WHO estimated >3 million deaths worldwide from COPD • ~5% global deaths • ~90% in low/middle income countries • ~65 million sufferers globally • In 1990, COPD was ranked 12th as a burden of disease; by 2020 it is projected to rank 5th • Burden probably under-estimated as not usually recognised/diagnosed until moderately advanced • Global burden/cost set to increase with increase in tobacco use in developing countries, ageing population, increasing cost of medical intervention

5. % Change in Age-Adjusted Death Rates, US, 1965-98 Proportion of 1965 Rate 3.0 Coronary Heart Disease Stroke Other CVD COPD All Other Causes 2.5 2.0 1.5 1.0 0.5 –59% –64% –35% +163% –7% 0 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 Source: NHLBI/NIH/DHHS

6. COPD: Gender

7. COPD: Ethnicity Deaths per 100,000 60 50 40 30 20 10 0 1960 1965 1970 1975 1980 1985 1990 1995 2000

8. COPD: Smoking Fletcher C, Peto R. Br Med J, 1977.(1):1645

9. COPD: Trends 1990 2020 Ischemic heart disease Cerebrovascular disease Lower resp infection Diarrheal disease Perinatal disorders COPD Tuberculosis Measles Road traffic accidents Lung cancer 3rd 6th Stomach Cancer HIV Suicide Murray & Lopez. Lancet 1997

10. Chronic Bronchitis • Nowadays, almost always due to smoking in UK • air pollution a significant cause elsewhere • Eg; in India, use of biomass fuels  circa 400-550 thousand premature deaths annually • Hypersecretion of mucous • Mucous gland hypertrophy • Loss of ciliated epithelia

11. Normal Airway Epithelium

12. Abnormal Airway Epithelium

13. Chronic Bronchitis • May also see… • squamous metaplasia of bronchial mucosa • submucosal oedema • lymphocytic infiltration • intraalveolar fibrosis • Leads to… • Inflammatory narrowing and fibrosis of bronchioles, impeding air flow • Goblet cell metaplasia leading to hypersecretion of mucous, further impeding air flow • Air sac distension and rupture (i.e. emphysema)

14. Emphysema • Dilation of acinar airspace due to destruction of interalveolarsepta • Due to proteolytic enzymes released from white cells during inflammation? • Common causes are smoking and air pollution •  low grade chronic pulmonary inflammation • Oxidants in smoke believed to inhibit normal anti-proteolytic activity of serum globulins

15. Normal vs Emphysema: gross lung structure

16. Emphysema: normal lung cross-section

17. Emphysema: diseased lung cross-section

18. Emphysema: Physiological Effects • Reduction in elasticity of lung tissue • restricts air flow to respiratory part of lung • causes airway collapse during expiration • Gas exchange area is reduced • Progressive dyspnoea and hypoxaemia • Development of cor pulmonale • Smaller surface area  • fewer capillaries, esp ‘in parallel’  increased resistance. • Hypoxaemia  vasoconstriction  • increased pulmonary artery pressure  • increased afterload on right ventricle  • right heart failure

19. COPD: Role of Inflammation • There is a chronic inflammatory process in COPD • But, it differs markedly from that seen in asthma • different inflammatory cells, • mediators, • inflammatory effects, • responses to treatment

20. COPD: Inflammatory Cells/Mediators • Cigarette smoke/irritants activate macrophages and airway epithelial cells •  neutrophil chemotactic factors • including interleukin-8 and leukotriene B4. • Neutrophils and macrophages release proteases • break down connective tissue in the lung parenchyma •  emphysema and mucous hypersecretion. • Proteases are normally counteracted by protease inhibitors, eg • (alpha)1-antitrypsin, • secretory leukoprotease inhibitor • tissue inhibitors of matrix metalloproteinases • Cytotoxic T cells (CD8+ lymphocytes) may also be involved in the inflammatory cascade. • MCP-1 is monocyte chemotactic protein 1 • released by and affects macrophages

21. COPD: Inflammatory Cells/Mediators

22. COPD: Protease-Antiprotease Imbalance • Proteases • Neutrophil elastase and proteinase 3 • neutrophil-derived serine proteases • Cathepsins • Can produce emphysema in laboratory animals. • Serine proteases •  mucus secretion (link to chronic bronchitis?) • Antiproteases • Inhibitors of serine proteases • (alpha)1-antitrypsin in lung parenchyma • airway-epithelium-derived secretory leukoprotease inhibitor in the airways • Three tissue inhibitors of matrix metalloproteinases (called TIMP-1, TIMP-2, and TIMP-3)

23. COPD: Protease-Antiprotease Imbalance • Balance tipped in favour of increased proteolysis • either an increase in proteases • or a deficiency of antiproteases • Balance set by noxious irritants (eg smoking) and host/genetic factors

24. COPD: Role of Oxidative Stress • Compounds generating oxidative stress • O2- superoxide anion, • H2O2- hydrogen peroxide, • OH• hydroxyl radical, • ONOO- peroxynitrate • Lead to… • …decreased antiprotease defences • …activation of nuclear factor-(kappa)B •  increased secretion of the cytokines interleukin-8 and tumor necrosis factor (alpha) • …increased production of isoprostanes • Oxidative stress marker • …other, direct effects on airway functions

25. COPD: Role of Oxidative Stress

27. Weight loss in COPD • Increased circulating levels of leptin, which may contribute to weight loss in these patients • Increased metabolism • loss of skeletal muscle and wasting of limb muscles • Skeletal-muscle weakness is a common feature of COPD • exacerbates dyspnea • The weakness is due to a combination of chronic hypoxia, immobility, and increased metabolic rate • Profound decrease in myosin heavy chain in skeletal muscles

28. COPD : Archetypes • Pink Puffer vs Blue Bloater • Extremes of a spectrum • ‘End Stage’ • Medical illustrations by Dr Frank Netter in 1950s

29. COPD : Archetypes – The Pink Puffer • COPD Type A – Emphysema • Hyperinflation/barrel chest • Tachypnea/pursed lips • Increased V/Q • Tachypnea / Low CO • Systemic hypoxia (low CO) • Weight loss • Problems eating & breathing at same time?

30. COPD : Archetypes – The Blue Bloater • COPD Type B – Chronic Bronchitis • Decreased V/Q • Poor ventilation / High CO • Cyanosis • CO2 retention • Acidosis • Pulmonary arteriolar constriction • Right heart failure

31. Tutorial – Gaseous Exchange

32. Gaseous Exchange • General factors affecting ‘flow’ • F = k * ΔP / R • K = constant • ΔP = delta P, ‘pressure gradient’ • R = ‘resistance’ • For exchange of respiratory gases in lungs… • R is related to cross-sectional area and thickness • K is related gas under consideration • Molecular weight • ‘velocity’ • Solubility

33. Gaseous Exchange • D = (A * ΔP * s) / (d * sqrt(MW) ) • D = diffusion rate • A = diffusion area • ΔP = partial pressure difference • s = solubility • d = diffusion distance • MW = molecular weight

34. Gaseous Exchange • Partial pressure • Pressure exerted by individual gas, independent of others • O2 = 20.93 % • If P = 760 mmHg, PO2 = 20.93/100 * 760 = 159 mmHg • Gas diffuses down a partial pressure gradient • When no gradient, no net (nett) movement • Gas can diffuse into water • By definition, when air/liquid in equilibrium (ie equal diffusion in and out), the partial pressures are the same • When partial pressures differ, the gas will move down its partial pressure gradient • Partial pressure should not be confused with concentration • Conc a function of pressure & ‘solubility’

35. Gaseous Exchange • A = 50 square metres • over which ~ 100 ml blood is ‘smeared’ – a monolayer! • d = down to 0.5 microns • Diffusing capacity of respiratory membrane… • Oxygen ~ 21 ml / min / mmHg • Normal pressure gradient is 11 mmHg  230 ml/min at rest • Carbon dioxide • Difficult to measure but >400 ml / min / mmHg • Can increase diffusing capacity by… • Increasing perfusion of under-perfused parts of lungs • Increasing cardiac output (blood normally equilibrates)

36. Gaseous Exchange • Some parts of lungs very poorly perfused at rest • Do not need that capacity, can exchange all the gases we need over a smaller area • Link between ventilation and perfusion • V/P (or V/Q) ratio • Approx 0.85 • Large V/P means more air ventilated than needed to service the blood flowing through the lungs • Wasted ventilation • Low V/P means more blood flowing than needed • Incomplete oxygenation • Physiologic shunt

37. Gaseous Exchange • ‘Ventilation’ of respiratory membrane a bit of a myth • As airways divide, each gets smaller… • But cross-sectional area gets greater • Thus, velocity of air gets smaller the further down the respiratory ‘tree’ • ‘Bulk flow’ near zero at the alveoli • Significant proportion of exchange is by diffusion • Helps keep alveolar composition fairly constant and exchange with blood fairly constant in face of intermittent breathing • Similar to a river  wide delta (eg Nile)