Respiratory System PDF - Cellular and Systematic Pathology

🧪 Respiratory System Module Cellular and Systematic Pathology Date @October 10, 2024 Lecturer Dr David Walsh Week Week 5 LECTURES Lecture 1 Respiratory Sys...

🧪 Respiratory System Module Cellular and Systematic Pathology Date @October 10, 2024 Lecturer Dr David Walsh Week Week 5 LECTURES Lecture 1 Respiratory System Respiratory Disorders - Obstructive Lecture 2 Asthma Lecture 3 Respiratory Disorders - restrictive RESPIRATORY SYSTEM Latest Figures Age related deaths from respiratory diseases in England and Wales indicate a link between areas of deprivation and such deaths. The figures also show that people from Glasgow have the lowest life expectancy in the UK. Respiratory System 1  Pulmonary System Vast area - epithelial surface the size of a tennis court Tracheobronchial tree is divided into the conducting airways and the respiratory airways. Conducting zone: Low resistance pathway for airflow. Contains cartilage as far as the bronchioles Gas exchange does not occur. Respiratory Zone: Contains alveoli and gas exchange occurs Basic structure of airways Respiratory System 2  The alveoli is where gas exchange takes place. The epithelium of the upper airway are pseudostratified columnar with cilia and goblet cells. Goblet cells secrete mucus which traps dust particles while the cilia waft the mucus (with the dust particles) to the mouth and nasal cavities. Respiratory System 3  Second defence against any infiltrates that get into lungs are macrophages. Macrophages protect the base of our lungs by engulfing dust, soot, smoke and bacteria. The image shows a macrophage capturing a green pathogen. Respiratory System 4  Gas exchange Occurs at alveolar walls which contain capillaries. There are about 300 million alveoli in the lungs. Surface area of around 70 sq metres Four layers separate blood from alveolar air 1) Type I alveolar cells 2) epithelial basement membrane 3) capillary basement membrane 4) capillary endothelial cells Oxygen Entry Oxygen enters the blood capillary by simple diffusion Respiratory System 5  Carbon dioxide leaves the blood by simple diffusion Respiratory System 6  Our lungs have considerable spare capacity WHAT DOES CO2 CONTORL? pH of the blood Lowering pH evokes contraction of airways Respiratory System 7  Widespread changes in pH alter all cellular activity Calibre of the airways Low CO2 causes bronchoconstriction Decreased pH impedes ciliary action and increases mucus viscosity Some top lung diseases Respiratory System 8  RESPIRATORY DISORDERS - OBSTRUCTIVE Obstructive - air flow is obstructed. Restrictive - lung expansion is restricted. Obstructive lung disease Mechanisms of obstruction excessive secretions chronic bronchitis (COPD), pulmonary oedema, aspiration. reduced airway diameter bronchoconstriction (asthma), inflammation (asthma, chronic bronchitis) loss of radial traction Reduction in parenchymal support of the airways due to loss of lung elastic recoil. Emphysema (COPD) In diseases like COPD, all of these can occur: Respiratory System 9  Airflow obstruction due to the loss of elastic recoil and airway narrowing. COPD 2nd most common cause of hospital admissions. 5th most common cause of death. Incidence increasing worldwide 1.2m diagnosed in UK, increase of 27% in last decade plus ≅ 2.2m undiagnosed 25,000 deaths p.a. in England and Wales Cigarette smoking the most important factor but 15% from workplace exposure (dusts, fumes, chemicals) Made up of chronic bronchitis and emphysema Respiratory System 10  COPD tends to form in a later age group (45-54). Up to about 74 years of age males and females remain about the same. Then, from 75 years and over more males suffer. Chronic Bronchitis Diagnosis based on presence of productive cough - Excessive mucus sufficient to cause excessive expectoration on most days for at least three months of the year for 2 or more successive years Principal aetiologic factor is inhalation of irritants cigarette smoke, pollutants Cough, dyspnea, respiratory infections We see: Inflammation and oedema of bronchial mucosa Hyperplasia and hypertrophy of submucosal mucous glands - semi-solid mucus plugs Hyperplasia and hypertrophy of smooth muscle - remodelling Reduction in cilia Respiratory System 11  Squamous metaplasia (cellular non-cancerous changes to the epithelia) The above image is a scanning electron micrograpph of bronchial epithelium in a patienyt with chronic brocnhitis, showing loss of cilia. Only a few clusters of clila remain on the cell surface. Respiratory System 12  Chronic bronchitis. Histologic section of bronchial mucosa in a patient with chronic bronchitis. There are increased numbers of goblet cells in the bronchial epithelium, and the basement membrane is markedly thickened. Obstruction reduced airway diameter (inflammation and oedema), excessive secretions (overproduction of mucus and loss of cilia) Infection accumulation of mucus Airtrapping from mucus obstruction Respiratory System 13  MECHANISM LEADING TO TRAPPED AIR LONG TERM CONSEQUENCES OF CHRONIC BRONCHITIS CIGARETTE SMOKERS Cigarettes act as an irritant which, with repeated exposure leads to chronic inflammation. Respiratory System 14  Occurs in cigarette smokers 10-12 years after starting - affects 10-15% of smokers Air pollution or industrial smoke may also cause this but 9 out of 10 patients are smokers. A normal situation we have a tissue injury and then an inflammatory response and the body repairs itself. However smokers have a persistent insult to lungs. CHANGE IN AIRFLOW Respiratory System 15  Slight changes in diameter of bronchioles leads to an increase in resistance to the fourth power. I.e large reduction in airflow. Course of illness is unpredictable but when functional impairment becomes severe, outlook is poor Emphysema alveolar destruction and enlargement Plus small and large airway inflammation and remodelling An imbalance between protease and antiprotease activity leads to alveolar destruction Triggered primarily by cigarette smoke Also caused by occupational and environmental pollutants e.g. biomass cooking of liquids and fuels, including wood, crops, animal dung, and coal. The loss of the capillaries means exchange of oxygen and CO2 is decreased. Inflammation in small airways leading to fibrosis, smooth muscle hyperplasia, and other chronic changes. Respiratory System 16  Enlargement of air spaces distal to terminal bronchioles with destructive changes in walls centrilobular affects respiratory bronchioles with initial preservation of alveolar ducts and sacs (associated with cigarettes and coal workers) panlobular involves alveoli associated with alpha1-antitrypsin deficiency (see later) Partly due to destruction of the pulmonary vascular bed and partly due to hypoxic pulmonary vasoconstriction, the pulmonary artery pressures rise resulting in cor pulmonale. Normal elasticity of the lungs, which allows for their expansion during inspiration and return to normal is severely impaired. Expiration requires effort instead of being passive. Extra work needs more oxygen. Lack of structural support means bronchi collapse during forced expiration - more obstruction, more air trapping Respiratory System 17  Hyperinflation: These changes, even in the early stages are irreversible. They may be so gross as to be seen with the naked eye About a third of the lung destroyed before symptoms are seen 20-30% of smokers susceptible There is no cure. Our lungs have considerable spare capacity Aetiology Cigarettes stimulate macrophages to release neutrophil chemoattractant: Respiratory System 18  Very large number of neutrophils in the lungs Excessive amounts of the proteolytic enzyme lysosomal elastase (and other enzymes) are released from these cells. Cytotoxic T-cells (CD8+) also arrive and add to the damage. Cigarettes may also reduce the activity of elastase inhibitors such as Alpha1 antitrypsin: Resynthesis of elastin may also be inhibited by cigarette smoke. All these result in destruction of elastin leading to emphysema A delicate balance of protease and antiprotease activity is required for proper lung maintenance – this balance is lost. In addition to inflammation, oxidative stress caused by cigarette smoke plays a significant role in emphysema Small and large airway damage Cigarette smoke contains oxidants that cause damage to epithelium Cigarette smoke activates airway epithelium and inflammatory cells to trigger airway remodelling Respiratory System 19  ALPHA1 ANTITRYPSIN Serum protein which inactivates proteolytic enzymes such elastase Concentration in blood is genetically determined Severe alpha1 antitrypsin deficiency - aggressive pulmonary emphysema in adolescence or early adulthood. No associated chronic bronchitis No cough or excess sputum production CAUSE OF DEATH Lack of enough functional tissue to sustain life Superimposed pulmonary infection (pneumonia) Leads to respiratory failure - acidosis, hypoxia, coma Cor pulmonale. Therapy for COPD Respiratory System 20  oxygen bronchodilators –anticholinergics (e.g. ipratropium bromide and new long-acting tiotropium) –ß2-adrenoceptor agonists (e.g. salbutamol, salmeterol) corticosteroids antibiotics Mucolytics Smoking cessation ASTHMA Statistics Children lose 8.5m school days/yr in UK plus up to 1.1 million working days lost (2020/2021) 368,000 people in Scotland: 1:14 -72,000 children, 296,000 adults 5.4m in UK inc. 1.1m children 1:12 receiving treatment ≈ 1,200 deaths/yr, mainly adults (approx. 3/day) Costs NHS 1b/yr 75% hospital admissions and 90% of deaths avoidable. 47% deaths due to prescribing errors Poor inhaled corticosteroid inhaler adherence may contribute to 24% of exacerbations and 60% of asthma-related hospitalisations Respiratory System 21  Triggers Genetic susceptibility then an environmental trigger to cause overt disease Triggers of asthma: Pollution Exposure to cigarette smoke Fewer Childhood infections? Premature birth/low birth weight Early exposure to allergens Processed foods? Occurs worldwide and incidence probably reflects both factors. Once a person has asthma, there are various triggers to an attack. Respiratory System 22  70-80% of asthmatic attacks are evoked by allergens (sometimes called extrinsic asthma). Other stimuli include bacterial and viral infections, cold air, dry air, pollutants and exercise. Causes / Symptoms Associated with increased contractility of airways to a variety of stimuli. Nevertheless, asthma is fundamentally a chronic inflammatory disease. Attacks vary from mild wheeze to attacks that cause suffocation. Clinical / Laboratory presentation: Inflammation Damage and denudation of the epithelium Bronchospasm Smooth muscle hypertrophy Basement membrane thickening Oedema Eosinophilia Increased mucus production Airway obstruction due to narrowing of airway (inflammation and bronchoconstriction) and excessive secretions (mucus) Allergic asthma (extrinsic) Allergen is inhaled Antigen presenting cells (dendritic cells, macrophages etc.) process the antigen and present fragments of it to the Th2-lymphocytes Th2 lymphocytes activate B-cells to form into plasma cells and secrete IgE. Respiratory System 23  B-cells can also be activated directly by antigen IgE locks into its receptors on mast cells (and other cells) The system is now primed Subsequent exposure to antigen leads to antigen linking to the IgE in place on the mast cell The mast cell degranulates and also forms active chemicals from its cells membrane Release of bronchoconstrictors - histamine, serotonin, kinins from vesicles Release of enzymes and oxidants Formation of prostaglandins and leukotrienes from membrane Bronchoconstriction, vascular permeability (oedema), mucus secretion Phase II (late phase) Chemotaxins cause the activation of inflammatory cells, particularly eosinophils (and other immune cells - Th-cells, macrophages, basophils, neutrophils) Respiratory System 24  Eosinophils release mediators that damage the epithelium. In severe or fatal asthma, there is explosive release of eosinophil granules - the mechanism by which this occurs is not clear. Late phase usually occurs 4 - 6h later. Eosinophils Designed to protect us from parasites Release potent chemical mediators including: Major basic protein Eosinophilic peroxidase Eosinophilic cationic protein These compounds damage the epithelium Early and late responses Respiratory System 25  Allergic Asthma The airway epithelium Immune barrier Diffusion barrier Physical barrier Mucociliary clearance Respiratory System 26  Releases bronchodilators Contains enzymes (esp. neutral endopeptidase (NEP)) to break down constrictor agents Protects sensory nerves Helps maintain normal tone in airway Respiratory System 27  Intrinsic Asthma Less well understood Allergen not the trigger (not IgE) Typically patient >40yr Triggers - virus, cold air, smoke, irritants, pollutants, gastroesophageal reflux, tobacco RESPIRATORY DISORDERS - RESTRICTIVE Restrictive lung disorders Extrinsic affecting system that generates respiratory movements Intrinsic Respiratory System 28  affecting lung tissue itself Acute Respiratory Distress Syndrome (ARDS) Interstitial Lung Disease (ILD) Restrictive disorders - extrinsic The chest wall, pleura, and respiratory muscles need to function normally for effective ventilation Diseases of these structures result in lung restriction, impaired ventilatory function, and respiratory failure EXTRINSIC RESTRICTION Defective thoracic framework kyphosis, scoliosis, kyphoscoliosis (Mixture of kyphosis and scoliosis) Respiratory muscle weakness muscular dystrophies Defective neuromuscular transmission botulism, myasthenia gravis Defective output from brain stem trauma, CNS depression Defective neural pathway to muscles neuropathies - poliomyelitis, Guillain-Barre KYPHOSIS: Respiratory System 29  SCOLIOSIS: Respiratory System 30  GULLIAN-BARRE SYNDROME Intrinsic restrictive disorders Diseases of the lung parenchyma. Inflammation/ scarring of the lung tissue - stiffening and reduced compliance Or in-filling of the air spaces with exudates and debris. Include idiopathic fibrotic diseases e.g. Idiopathic pulmonary fibrosis Connective tissue disease e.g. Scleroderma Drug-induced lung disease e.g. Chemotherapy agents, Antibiotics Inorganic dust exposure e.g. Asbestosis Respiratory System 31  Primary diseases of the lungs e.g. Sarcoidosis Pneumonia SARCOIDOSIS: Acute respiratory distress syndrome (ARDS) An Intrinsic restrictive lung disease Also called adult respiratory distress syndrome Response to various types of lung injury Injury leads to diffuse inflammation of the parenchyma and impaired gas exchange Possible causes ARDS including: 1. Infection (common cause) - Pneumonia (especially viral) or sepsis 2. Shock - esp. septic and traumatic 3. Aspiration /inhalation - Gastric contents, near drowning (esp. salt). 4. Systemic inflammatory response syndrome (common cause) - e.g. pancreatitis, overdose (e.g., heroin, salicylates) Respiratory System 32  Onset follows injury by hours to two days Exudative phase is the initial phase injury to the endothelium and epithelium, inflammation and fluid exudation Respiratory System 33  Fibroproliferative phase influx and proliferation of fibroblasts and other cellular elements. Injury may start to resolve or become persistent Patients may present with minimal symptoms e.g.. mild tachypnea Followed by severe respiratory distress Fatal in 30-40% of cases Death from multi-organ failure rather than just lung failure Pneumonia An Intrinsic restrictive lung disease that can lead to ARDS An inflammation of the lungs commonly caused by bacteria, viruses or fungi. Can also be caused by chemicals, aspiration or autoimmune disease Involving one or two lobes of a lung - lobar pneumonia Common causative organisms: Common symptoms: Cough with Sputum (purulent and blood tinged) Dyspnoea Pleuritic chest pain (stabbing pain exacerbated by breathing and coughing) Crackles (auscultation) Respiratory System 34  Dullness (percussion) Fever (39.5-40.5oC) and shaking chills Confusion in the elderly Cyanosis fatigue Pathophysiology / pathology Microorganisms overwhelm normal defences (mucociliary clearance, macrophage activity) The host response (rather than the initiating infection) causes damage to the airways and the subsequent symptoms Inflammatory response involves release of mediators e.g. interleulin-1 and tumour necrosis factor α (TNFα) - fever Alveolar macrophages release chemokines such as interleukin-8 and GM-CSF to attract neutrophils – purulent sputum Erythrocytes may cross alveolar barrier - haemoptysis Capillary leak results in fluid moving into alveoli, - rales (rattling sound) and hypoxaemia Dyspnoea due to: Decreased compliance due to capillary leak and dilution of surfactant Hypoxaemia Respiratory System 35  Phases Initial: oedema, and often bacteria in the alveoli Second: erythrocytes and neutrophils in the intra-alveolar exudate Third: neutrophils are the predominant cell in exudate, bacteria have disappeared so infection contained. Gas exchange improves Last: macrophages are the predominant cell, debris of neutrophils and bacteria has been cleared and inflammation subsided Prognosis Depends on: Patient's age Respiratory System 36  Comorbidities Site of treatment (inpatient or outpatient) Mortality rate for the outpatients