Obstructive Airway Diseases Chronic (Obstructive) Bronchitis Emphysema Bronchiectasis Asthma

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 for 2 years Emphysema is permanent enlargement of the airspaces distal to terminal bronchioles a result of alveolar wall destruction Chronic Bronchitis & Emphysema

A disease state characterised by airflow limitation that is not fully reversible compounded by effects of emphysema on gas exchange at resp membrane Airflow limitation is usually both progressive and associated with abnormal inflammatory response of lungs to noxious particles or gases primary cause is tobacco smoke COPD: Definition

COPD is the 4 th 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 12 th as a burden of disease; by 2020 it is projected to rank 5 th 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 COPD: Facts

% Change in Age-Adjusted Death Rates, US, Proportion of 1965 Rate –59% –64% –35% +163% –7% Coronary Heart Disease Coronary Heart Disease Stroke Other CVD COPD All Other Causes All Other Causes Source: NHLBI/NIH/DHHS

COPD: Gender

COPD: Ethnicity 60 Deaths per 100,

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

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

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

Normal Airway Epithelium

Abnormal Airway Epithelium

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) Decreased lung compliance (fibrosis) Chronic Bronchitis

Dilation of acinar airspace due to destruction of interalveolar septa 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 Emphysema

Normal vs Emphysema: gross lung structure

Emphysema: normal lung cross-section

Emphysema: diseased lung cross-section

Reduction in elasticity (compliance) of lung tissue remodelling  airway/ductal collapse during expiration interferes with air flow to/from respiratory part of lung Gas exchange area is also reduced Progressive dyspnoea and hypoxaemia Development of cor pulmonale Smaller surface area  fewer capillaries, esp ‘in parallel’  increased resistance. Hypoxaemia  vasoconstriction (reverse of other tissues)  increased pulmonary artery pressure  increased afterload on right ventricle  right heart failure Emphysema: Physiological Effects

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 COPD: Role of Inflammation

Cigarette smoke/irritants activate macrophages and airway epithelial cells  neutrophil chemotactic factors including interleukin-8 and leukotriene B 4. 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 COPD: Inflammatory Cells/Mediators

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) Elafin (skin-derived antileukoprotease – SKALP) 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 COPD: Protease-Antiprotease Imbalance

Compounds generating oxidative stress H 2 O 2 hydrogen peroxide, O 2 - superoxide anion, OH hydroxyl radical (unpaired electron), 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 COPD: Role of Oxidative Stress

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

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

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?

COPD : Archetypes – The Blue Bloater COPD Type B – Chronic Bronchitis Decreased V/Q Poor ventilation / High CO Cyanosis CO 2 retention Acidosis Pulmonary arteriolar constriction Right heart failure