Respiratory System PDF Fall 2023

10/2/2023 Respiratory System Dr Neha Mishra Kumar V, Abbas AK, & Astor, JC. Robbins Basic Pathology, 10th edition Zachary JF, and McGavin MD. Pathologic Basis of Veterinary Disease, 6th edition, Elsevier, 2017 Young et al. Wheater’s Functional Histology: A Text and Colour Atlas, 5th or 6th ed. 1...

10/2/2023 Respiratory System Dr Neha Mishra Kumar V, Abbas AK, & Astor, JC. Robbins Basic Pathology, 10th edition Zachary JF, and McGavin MD. Pathologic Basis of Veterinary Disease, 6th edition, Elsevier, 2017 Young et al. Wheater’s Functional Histology: A Text and Colour Atlas, 5th or 6th ed. 1 Respiration • Respiration involves two interrelated processes: • cellular respiration and mechanical respiration • Cellular respiration involves the biochemical processes that generate energy (ATP) • e.g. glycolysis and oxidative phosphorylation (mitochondria) • Mechanical respiration moves air and allows for gas exchange by: • Inhalation of air • Warm and moisten air, and remove particulate matter through action of mucociliary escalator (Goblet cells) • Gas exchange: oxygen combines with hemoglobin in RBC’s at the same time that carbon dioxide is transferred from blood to air • Exhalation of air Serous gland: secrete watery secretions, moistenes the air Goblet cells secrete mucous but that does not help much with moistening the air 2 Goblet cells: Mucociliary escalator Organization Nasal mucosa supplied by extensive capillary to heat air. Trachea own to intrapulmonary bronchus is the conducting portion of the respiratory system • Upper respiratory tract • Nasal cavity (containing nasal turbinates), paranasal sinuses, nasopharynx and larynx • Function: conduct, warm & humidify air; also site of olfaction; vocalization Nasal cavities, Nasal turbinates, Nasopharyx and larynx Para nasal sinuses. 3 1 10/2/2023 Organization • Lower respiratory tract Trachea, primary secondary tertiary Branch into the bronchioles , then the alveoli 4 • Trachea, bronchi (primary, secondary, tertiary), bronchioles, alveoli • Function: • proximal region conducts and removes particulate material • gas exchange in terminal region Terminal and respiratory bronchioles is where gas exchange occurs Then it opens into Alveolar ducts Organization • Can also divide respiratory tract into conductive and exchange portions • Conductive portion extends from nasal cavity to terminal bronchioles • Exchange portion begins with respiratory bronchioles and alveolar ducts and terminates with alveoli 5 Nasal cavity • Functions: conducting, filtering, humidifying, warming air and olfaction • Beginning of the conductive portion of respiratory tract • Nasal cavity divided into respiratory and olfactory regions Hyaline cartilage Turbinate Nasal septum 6 2 10/2/2023 Respiratory region • Nasal cavity divided in two by nasal septum (hyaline cartilage) • Turbinates are scrolls of bone lined by nasal mucosaRespiratory epithelium is • Increase surface area for heat and water exchange • Nasal mucosa is pseudostratified ciliated columnar epithelium with numerous goblet cells (respiratory epithelium) pseudostratified colomnuar, ciliated, with goblet cells. Increase area for heat and water exchange • Mucosa supported by very vascular lamina propria with The connective tissue supporting the respiratory epithelium mucous and serous glands • Mucous traps particles, cilia move particles out • Serous gland secretions humidify air Serous gland Look more dark Mucus gland is more foamy • Thin‐walled venules exchange heat with air • warms incoming air 7 Sinsus Turbinates Septum 8 Pseudostratified just means it looks like its multilayered but its just because nucleus are all on different levels Nasal mucosa Goblet cell Cilia Serous Serous gland Vein 9 3 10/2/2023 Olfactory region • Olfactory receptor cell • Bipolar neurons with long non‐motile cilia (80 um) Olfactory receptor shaped like cilia • Basal processes are axons  penetrate BM  penetrate cribriform plate in ethmoid bone  form cranial nerve I  synapse in olfactory bulb of brain • Clustered by chemical sensitivity, integrate chemical signals then depolarize for impulse generation • Sustentacular cell • Supporting epithelial cell • Top layer of nuclei belong to these cells, possess long microvilli • Basal cell • Stem cells for olfactory and sustentacular cells • Lamina propria • Loose connective tissue containing blood vessels, afferent nerve fibers and serous glands 10 11 Respiratory 12 Olfactory epithelium: multiple layers of pseudo. No goblet cells. Sustenticular cells cilia is much shorter but where its long its longer than respiratory cilia (not continuous) 4 10/2/2023 Paranasal sinuses • Spaces continuous with nasal cavities • Located in cranial bones, e.g. maxillary, frontal, ethmoid, sphenoid • Provides increased surface for humidification of air • can be a location of infections Sinusitis (inflammation, infection) • Lined by respiratory epithelium 13 The paranasal sinuses are only lined by respiratory epithelium Nasopharynx • Located dorsal to soft palate • Lined by respiratory epithelium • Lamina propria contains large masses of lymphoid tissue and lymphatics • provides immune surveillance at the portals of entry of the respiratory and gastrointestinal systems • prominent in children and adolescents and forms the nasopharyngeal tonsil, aka adenoid Nasal sinus is the naso pharynx. this is where esophagus and respiratory system meet, (pharyngeal portion). Lamina proprietor here contains masses of lymphoid tissue and lymphatics. provides immune surveillance. prominent infections in adolescents and children. Nasopharyngeal tonsil / adenoid 14 Larynx • Connects pharynx to trachea • Caudal/distal extent of the upper respiratory tract • Framework of elastic cartilage lined by mucous membrane • Combination of respiratory epithelium and non‐keratinized stratified squamous epithelium • Also contains ligaments and striated muscles Helps initiate movement • (Elastic and connective tissue project into the glottis (vibrate as air passes) 15 Vocal cords or folds • Project into glottis • Vibrate as air passes between them to make sound • Lined by stratified squamous epithelium Larynx: elastic septum: hyaline 5 10/2/2023 Trachea • Beginning of lower respiratory tract • Extends from larynx to carina (site of bifurcation into primary bronchi • Continuously open, flexible tube of hyaline cartilage and fibroelastic tissue • Expansion and extension during inspiration, recoil during expiration • C‐shaped rings of hyaline cartilage • Bands of smooth muscle (trachealis muscle) join the ends of the rings to reduce diameter when necessary • In birds, tracheal rings are complete, i.e. O‐shaped instead of C‐shaped 16 Cartilage Lamina propria Trachealis muscle 17 Trachea • Lined by respiratory epithelium • Pseudostratified columnar ciliated • Goblet cells • Apical cytoplasm contains dense aggregation of mucigen granules • composed of proteoglycans • Stainable by PAS method • Supply mucous component of mucociliary escalator • Lamina propria highly vascularized Trachealis muscle Important stains: brighten up goblet cells • May contain aggregates of lymphocytes (MALT) Mucosa associated lymphoid tissue 18 6 10/2/2023 Trachea Lamina propria • Submucosa contains seromucous glands • Glands decrease in number in lower parts of trachea • Mucous component pale staining (like goblet cells) • Serous component dark staining • Submucosal connective tissue merges with perichondrium of hyaline cartilage • Adventitia on the outer surface Serous glands 19 Serous mucus glands Trachealis muscle 20 Bronchi • • • Start at tracheal bifurcation (carina) Enter lungs Primary (main stem) bronchi  Secondary (lobar)  Tertiary (segmental)  Bronchioles Lack of cartilage in the bronchioles 21 7 10/2/2023 Cilia Goblet cells 22 Changes in airways with progression into the lung 1. Gradual decrease in tubular diameter 2. Height of epithelial cells is reduced • Less pseudostratification, more simple columnar And cuboidal into simple squamous 3. Progressively fewer goblet cells 4. Increase in smooth muscle relative to diameter from trachea to bronchioles 5. Gradual reduction and loss of cartilage 6. Submucosa thins and seromucous glands become sparse No cartilage but replacement for smooth muscle 23 Alveoli Cartilage In one of the bronchus branches 24 Pseudo stratification of the columnar cells, but becoming less tall as they get closer to the terminal bronchioles 8 10/2/2023 Bronchioles • Airways of less than 1 mm diameter • No cartilage, no submucosal glands • Epithelium is simple ciliated columnar to cuboidal with few goblet cells • Wall composed of smooth muscle • Smooth muscle tone controls diameter and resistance to airflow Multi factorial • Clara cells replace mucous cells in terminal and respiratory bronchioles • Tall columnar cells with apical secretory granules Detoxify chemicals, also protyolytic enzymes, and breaks down mucin ( to prevent thick mucus clogging alveoli. 25 Clara cells are only found in terminal bronchioles and alveoli, they replace g Also pluripotent Not cilliated 26 Clara Cells Just before the alveoli, very hypereosinophilic and domed like shape • Found in terminal and respiratory bronchioles • Become predominant epithelial cell in distal respiratory bronchioles • Functions of Clara cells: • Produce one of the components of surfactant • Act as stem cells, i.e. divide and differentiate to replace other cell types lost or damaged • Contain enzyme systems to detoxify chemicals, digest proteins (proteolytic) and breakdown mucin (mucolytic) 27 9 10/2/2023 Where are pneumocystis in this image? • Neuroendocrine cells present in bronchiolar epithelium • Part of diffuse neuroendocrine system • Dense core granules contain peptide hormones that regulate smooth muscle tone in airway and vessel walls • Increased smooth muscle tone = bronchoconstriction • Decreases air flow • Occurs with asthma, allergic reactions Bronchoconstriction!!! Chromagranin: Stains endocrine and neuroendocrine cells 28 Terminal respiratory tree • Terminal bronchioles are smallest diameter passages of the conducting portion of the respiratory tract • Divide into respiratory bronchioles • Respiratory bronchioles interrupted by alveoli in their walls • Beginning of gas exchange portion • No goblet cells, lined by ciliated cuboidal cells and increasing numbers of non‐ciliated Clara cells (predominate distally) • Respiratory bronchioles divide into several alveolar ducts • Alveolar ducts have numerous alveoli opening along their length • Alveolar ducts end in alveolar sacs • Alveolar sacs open into several alveoli • Alveoli are pockets lined by flattened epithelial cells, pneumocytes, surrounded by pulmonary capillaries Line alveoli 29 Visceral Pleura: squamous epithelium Parietal pleura: lines thoracic cavity ( Trachea > Bronchi ‐3 sizes) > Bronchioles > Terminal bronchiole > Respiratory bronchiole > Alveolar duct > Alveolar sac > ALVEOLI 30 Which of the following is true in the resp track: Goblet cell decreases Ciliated cells become non ciliated Columnar pseudostratified becomes less stratified and then become columnar to cuboidal Smooth muscle will be increasing as you go from trachea to bronchioles (All true) 10 10/2/2023 Terminal bronchule Respiratory bronchiole Alveolar ducts Alveolar sacs Normal 31 Cuboidal Clara cells Alveolar interstitium Respiratory bronchioles 32 Alveoli • Function in gas exchange • Wall is called an alveolar septum • composed of central alveolar capillary, supported by sparse network of elastin and collagen • lined on each side by epithelial cells of adjacent alveoli • Lining epithelial cells called pneumocytes Less abundant but covers more surface • Type I area, flat and spread out • Type II More in number but covers less surface area (cuboidal) counterpart of the Clara cells, important in regenerating type 1 pneumocystes 33 11 10/2/2023 34 Alveoli • Type I pneumocytes • large squamous cells form continuous lining • line vast majority of alveolar surface and constitute gas diffusion barrier • Type II pneumocytes • rounded cell with round nucleus Cuboidal • occupy about 5% of surface area but comprise 60% of cells • secrete surfactant • reduces surface tension across alveoli to prevent collapse • retain ability to divide and can also differentiate into type I pneumocytes 35 36 12 10/2/2023 Macrophages Healthy alveoli 37 Resident macrophages (alveolar macrophages (to scavenge for any foreign materials) Type II pneumocytes • Also known as surfactant cells • Nuclei are large and round with dispersed chromatin • Abundant granular eosinophilic cytoplasm • Cytoplasm contains lamellar bodies • membrane‐bound, lamellated structures on EM • contain phospholipid • Discharge phospholipid by exocytosis into the alveolar space • Combines with other secretory products (e.g. products of bronchiolar Clara cells) • Forms layer of surfactant at the epithelium/air interface • Overcomes the effects of surface tension and prevents alveolar surfaces from adhering to one another 38 Lamellar bodies Laminar secrete: Phospholipids, Surfactant Detoxification Lamellar/ laminated? bodies Fibroblast nucleus 39 13 10/2/2023 Alveolar septum • Type II pneumocytes typically located at the branching point of the alveolar septum 40 Air‐blood barrier • • Diffusion barrier between blood and alveolar air Blood vessel component • • • • Capillaries form plexus around each alveolus, running through the alveolar septa BM of endothelium is applied to BM of epithelium Epithelial component • Type I pneumocytes spread across the vast majority of the alveolar surface Air‐blood barrier consists of the following: 1. Attenuated cytoplasm of the type I pneumocyte 2. Fused basement membrane 3. Thin cytoplasm of the capillary endothelial cell 41 Pulmonary connective tissue • The interstitium • Thin layer beneath BM of pneumocytes and surrounding blood vessels • Reticulin, collagen, elastin fibers • Large amount of elastin in the alveolar walls which is condensed at the opening of alveoli to form a supporting ring 42 14 10/2/2023 Pulmonary Components of Mononuclear Phagocyte System • Alveolar macrophage located in alveoli on alveolar surface • Phagocytose and remove unwanted material from air spaces, e.g. inhaled particulates (carbon/smoke), bacteria • Pulmonary interstitial macrophage located stationary in the connective tissue between alveoli 43 Black carbon particles 44 Pleura • Lining covering the lung and the pleural cavities • Visceral pleura covers lungs • Parietal pleura lines thoracic wall • Consists of a thin flattened mesothelium supported by fibroelastic connective tissue 45 15 10/2/2023 Pulmonary blood vessels • Pulmonary arteries • Carry de‐oxygenated blood from right heart • Give rise to alveolar capillaries that form the blood‐air‐barrier and are involved in gas exchange • Bronchial arteries • Minor blood supply to thick‐walled structures in lung, e.g. bronchi • Oxygenated blood • Pulmonary veins • Return oxygenated blood to left heart 46 16 10/4/2023 Respiratory System Dr Neha Mishra Kumar V, Abbas AK, & Astor, JC. Robbins Basic Pathology, 10th edition Zachary JF, and McGavin MD. Pathologic Basis of Veterinary Disease, 6th edition, Elsevier, 2017 Young et al. Wheater’s Functional Histology: A Text and Colour Atlas, 5th or 6th ed. 1 Respiration • Respiration involves two interrelated processes: • cellular respiration and mechanical respiration • Cellular respiration involves the biochemical processes that generate energy (ATP) • e.g. glycolysis and oxidative phosphorylation (mitochondria) • Mechanical respiration moves air and allows for gas exchange by: • Inhalation of air • Warm and moisten air, and remove particulate matter through action of mucociliary escalator • Gas exchange: oxygen combines with hemoglobin in RBC’s at the same time that carbon dioxide is transferred from blood to air • Exhalation of air 2 Organization • Upper respiratory tract • Nasal cavity (containing nasal turbinates), paranasal sinuses, nasopharynx and larynx • Function: conduct, warm & humidify air; also site of olfaction; vocalization 3 1 10/4/2023 Organization • Lower respiratory tract • Trachea, bronchi (primary, secondary, tertiary), bronchioles, alveoli • Function: • proximal region conducts and removes particulate material • gas exchange in terminal region 4 Organization • Can also divide respiratory tract into conductive and exchange portions • Conductive portion extends from nasal cavity to terminal bronchioles • Exchange portion begins with respiratory bronchioles and alveolar ducts and terminates with alveoli 5 Nasal cavity • Functions: conducting, filtering, humidifying, warming air and olfaction • Beginning of the conductive portion of respiratory tract • Nasal cavity divided into respiratory and olfactory regions 6 2 10/4/2023 Respiratory region • Nasal cavity divided in two by nasal septum (hyaline cartilage) • Turbinates are scrolls of bone lined by nasal mucosa • Increase surface area for heat and water exchange • Nasal mucosa is pseudostratified ciliated columnar epithelium with numerous goblet cells (respiratory epithelium) • Mucosa supported by very vascular lamina propria with mucous and serous glands • Mucous traps particles, cilia move particles out • Serous gland secretions humidify air • Thin‐walled venules exchange heat with air • warms incoming air 7 8 Nasal mucosa 9 3 10/4/2023 Olfactory region • Olfactory receptor cell • Bipolar neurons with long non‐motile cilia (80 um) • Basal processes are axons  penetrate BM  penetrate cribriform plate in ethmoid bone  form cranial nerve I  synapse in olfactory bulb of brain • Clustered by chemical sensitivity, integrate chemical signals then depolarize for impulse generation • Sustentacular cell • Supporting epithelial cell • Top layer of nuclei belong to these cells, possess long microvilli • Basal cell • Stem cells for olfactory and sustentacular cells • Lamina propria • Loose connective tissue containing blood vessels, afferent nerve fibers and serous glands 10 11 12 4 10/4/2023 Paranasal sinuses • Spaces continuous with nasal cavities • Located in cranial bones, e.g. maxillary, frontal, ethmoid, sphenoid • Provides increased surface for humidification of air • can be a location of infections • Lined by respiratory epithelium 13 Nasopharynx • Located dorsal to soft palate • Lined by respiratory epithelium • Lamina propria contains large masses of lymphoid tissue and lymphatics • provides immune surveillance at the portals of entry of the respiratory and gastrointestinal systems • prominent in children and adolescents and forms the nasopharyngeal tonsil, aka adenoid 14 Larynx • Connects pharynx to trachea • Caudal/distal extent of the upper respiratory tract • Framework of elastic cartilage lined by mucous membrane • Combination of respiratory epithelium and non‐keratinized stratified squamous epithelium • Also contains ligaments and striated muscles • Vocal cords or folds • Project into glottis • Vibrate as air passes between them to make sound • Lined by stratified squamous epithelium 15 5 10/4/2023 Trachea • Beginning of lower respiratory tract • Extends from larynx to carina (site of bifurcation into primary bronchi • Continuously open, flexible tube of hyaline cartilage and fibroelastic tissue • Expansion and extension during inspiration, recoil during expiration • C‐shaped rings of hyaline cartilage • Bands of smooth muscle (trachealis muscle) join the ends of the rings to reduce diameter when necessary • In birds, tracheal rings are complete, i.e. O‐shaped instead of C‐shaped 16 17 Trachea • Lined by respiratory epithelium • Pseudostratified columnar ciliated • Goblet cells • Apical cytoplasm contains dense aggregation of mucigen granules • composed of proteoglycans • Stainable by PAS method • Supply mucous component of mucociliary escalator • Lamina propria highly vascularized • May contain aggregates of lymphocytes (MALT) 18 6 10/4/2023 Trachea • Submucosa contains seromucous glands • Glands decrease in number in lower parts of trachea • Mucous component pale staining (like goblet cells) • Serous component dark staining • Submucosal connective tissue merges with perichondrium of hyaline cartilage • Adventitia on the outer surface 19 20 Bronchi • • • Start at tracheal bifurcation (carina) Enter lungs Primary (main stem) bronchi  Secondary (lobar)  Tertiary (segmental)  Bronchioles 21 7 10/4/2023 22 Changes in airways with progression into the lung 1. Gradual decrease in tubular diameter 2. Height of epithelial cells is reduced • Less pseudostratification, more simple columnar 3. Progressively fewer goblet cells 4. Increase in smooth muscle relative to diameter from trachea to bronchioles 5. Gradual reduction and loss of cartilage 6. Submucosa thins and seromucous glands become sparse 23 24 8 10/4/2023 Bronchioles • Airways of less than 1 mm diameter • No cartilage, no submucosal glands • Epithelium is simple ciliated columnar to cuboidal with few goblet cells • Wall composed of smooth muscle • Smooth muscle tone controls diameter and resistance to airflow • Clara cells replace mucous cells in terminal and respiratory bronchioles • Tall columnar cells with apical secretory granules 25 26 Clara Cells • Found in terminal and respiratory bronchioles • Become predominant epithelial cell in distal respiratory bronchioles • Functions of Clara cells: • Produce one of the components of surfactant • Act as stem cells, i.e. divide and differentiate to replace other cell types lost or damaged • Contain enzyme systems to detoxify chemicals, digest proteins (proteolytic) and breakdown mucin (mucolytic) 27 9 10/4/2023 • Neuroendocrine cells present in bronchiolar epithelium • Part of diffuse neuroendocrine system • Dense core granules contain peptide hormones that regulate smooth muscle tone in airway and vessel walls • Increased smooth muscle tone = bronchoconstriction • Decreases air flow • Occurs with asthma, allergic reactions 28 Terminal respiratory tree • Terminal bronchioles are smallest diameter passages of the conducting portion of the respiratory tract • Divide into respiratory bronchioles • Respiratory bronchioles interrupted by alveoli in their walls • Beginning of gas exchange portion • No goblet cells, lined by ciliated cuboidal cells and increasing numbers of non‐ciliated Clara cells (predominate distally) • Respiratory bronchioles divide into several alveolar ducts • Alveolar ducts have numerous alveoli opening along their length • Alveolar ducts end in alveolar sacs • Alveolar sacs open into several alveoli • Alveoli are pockets lined by flattened epithelial cells, pneumocytes, surrounded by pulmonary capillaries 29 ( Trachea > Bronchi ‐3 sizes) > Bronchioles > Terminal bronchiole > Respiratory bronchiole > Alveolar duct > Alveolar sac > ALVEOLI 30 10 10/4/2023 31 32 Alveoli • Function in gas exchange • Wall is called an alveolar septum • composed of central alveolar capillary, supported by sparse network of elastin and collagen • lined on each side by epithelial cells of adjacent alveoli • Lining epithelial cells called pneumocytes • Type I • Type II 33 11 10/4/2023 Alveoli • Type I pneumocytes • large squamous cells form continuous lining • line vast majority of alveolar surface and constitute gas diffusion barrier • Type II pneumocytes • rounded cell with round nucleus • occupy about 5% of surface area but comprise 60% of cells • secrete surfactant • reduces surface tension across alveoli to prevent collapse • retain ability to divide and can also differentiate into type I pneumocytes 34 Alveoli • Type I pneumocytes • large squamous cells form continuous lining • line vast majority of alveolar surface and constitute gas diffusion barrier • Type II pneumocytes • rounded cell with round nucleus • occupy about 5% of surface area but comprise 60% of cells • secrete surfactant • reduces surface tension across alveoli to prevent collapse • retain ability to divide and can also differentiate into type I pneumocytes 35 36 12 10/4/2023 37 Type II pneumocytes • • • • Also known as surfactant cells Nuclei are large and round Abundant granular eosinophilic cytoplasm Cytoplasm contains lamellar bodies • membrane‐bound, lamellated structures on EM • contain phospholipid • Discharge phospholipid by exocytosis into the alveolar space • Combines with other secretory products (e.g. products of bronchiolar Clara cells) • Forms layer of surfactant at the epithelium/air interface • Overcomes the effects of surface tension and prevents alveolar surfaces from adhering to one another 38 39 13 10/4/2023 Alveolar septum • Type II pneumocytes typically located at the branching point of the alveolar septum 40 Air‐blood barrier • • Diffusion barrier between blood and alveolar air Blood vessel component • • • • Capillaries form plexus around each alveolus, running through the alveolar septa BM of endothelium is applied to BM of epithelium Epithelial component • Type I pneumocytes spread across the vast majority of the alveolar surface Air‐blood barrier consists of the following: 1. Attenuated cytoplasm of the type I pneumocyte 2. Fused basement membrane 3. Thin cytoplasm of the capillary endothelial cell 41 Pulmonary Components of Mononuclear Phagocyte System • Alveolar macrophage located in alveoli on alveolar surface • Phagocytose and remove unwanted material from air spaces, e.g. inhaled particulates (carbon/smoke), bacteria • Pulmonary interstitial macrophage located stationary in the connective tissue between alveoli 42 14 10/4/2023 Smokers lung: Macrophages filled with particles. 43 Pleura Mesothelium • Lining covering the lung and the pleural cavities • Visceral pleura covers lungs • Parietal pleura lines thoracic wall • Consists of a thin flattened mesothelium supported by fibroelastic connective tissue 44 Pulmonary blood vessels • Pulmonary arteries • Carry de‐oxygenated blood from right heart • Give rise to alveolar capillaries that form the blood‐air‐barrier and are involved in gas exchange • Bronchial arteries • Minor blood supply to thick‐walled structures in lung, e.g. bronchi • Oxygenated blood • Pulmonary veins • Return oxygenated blood to left heart 45 15 10/4/2023 Lung defense mechanisms Tertiary bronchioles also has mucocilliary escalator Plasma cells in the interstitium, secrete immunoglobulin A and G. A will be coming from Club cellsmucosa. G will be coming from the blood vessels. Go And trigger immune response 46 Lung Pathology 47 Atelectasis (Collapse) • Atelectasis is incomplete expansion of lungs (neonatal), or. collapse of previously inflated air space (acquired) • Results in circulation of inadequately oxygenated blood, giving rise to ventilation‐perfusion imbalance and hypoxia 48 16 10/4/2023 Compressed 49 Atelectasis is lung collapse : there are 3 types Atelectasis (Collapse) Acquired atelectasis • Resorption Atelectasis occurs when obstruction prevents air from reaching distal airways • most common cause is obstruction by mucus plug in bronchus • Compression Atelectasis is associated with accumulation of fluid, blood or air within pleural cavity which collapse the adjacent lung (pleural effusion, pneumothorax) • Contraction Atelectasis occurs when local or generalized fibrotic changes in lung or pleura hamper expansion and increase elastic recoil during expiration 50 Collapsed alveoli 51 17 10/4/2023 Emphysema • Condition of lung • irreversible enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their (e.g. alveolar) walls without fibrosis • Characterized by mild chronic inflammation • epithelium and macrophages release leukotriene B4, TNF, IL‐8 • Macrophages, CD8+ & CD4+ T lymphocytes • Recruitment of neutrophils • Destruction of connective tissue a consequence of imbalance of protease‐antiprotease and oxidative stress • Neutrophils are principle source of proteases • Inflammatory cells produce ROS • Clear association between heavy cigarette smoking and emphysema 52 Figure 12‐08. Pulmonary emphysema. There is marked enlargement of air spaces, with destruction of alveolar septa but without fibrosis. Note presence of black anthracene pigment. Figure 12‐09. Bullous emphysema with large apical and subpleural bullae. (From the Teaching Collection of the Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.) 53 Acute Respiratory Distress Syndrome (ARDS) • A manifestation of severe acute lung injury • In many cases, due to a combination of predisposing conditions e.g. shock, oxygen therapy, sepsis. • Clinical syndrome of progressive respiratory insufficiency associated with inflammation‐induced increase in vascular permeability, edema and epithelial cell death. • Associated with direct injury to the lung or systemic disorders • diffuse alveolar damage • rapid onset of life threatening respiratory insufficiency  cyanosis & hypoxemia 54 18 10/4/2023 Pathogenesis of ARDS acute injury to the alveolar epithelium and capillary endothelium → increasing inflammation and pulmonary damage • Endothelial activation ‐ dt pneumocyte damage or circulating inflammatory mediators • Neutrophils and their products play a crucial role (ROS, proteases, platelet‐activating factor, leukotrienes) • MIF 55 Histopathology of ARDS Early (exudative) stage: edema, epithelial necrosis, accumulation of neutrophils, hemorrhage, and hyaline membranes, which consist of inspissating protein/fibrin‐rich edema fluid admixed with remnants of necrotic alveolar epithelial cells Organizing stage: marked proliferation of type II pneumocytes; resorption of the hyaline membranes and thickening of the alveolar septa by inflammatory cells, fibroblasts and collagen Hyaline membrane Figure 13‐3A. Diffuse alveolar damage in acute lung injury and acute respiratory distress syndrome. Some alveoli are collapsed; others are distended. Many are lined by bright pink hyaline membranes (arrow). B, The healing stage is marked by resorption of hyaline membranes with thickening of alveolar septa containing inflammatory cells, fibroblasts, and collagen. Numerous reactive type II pneumocytes also are seen at this stage (arrows), associated with regeneration and repair. A, 56 Outcome of ARDS • Mortality rate approximately 60% • deaths attributable to sepsis or multiorgan failure or direct lung injury • improvements in therapy for sepsis, mechanical ventilation and supportive care has reduced mortality two approximately 40% in US. • Survivors may have persistent impairment. 57 19 10/6/2023 Outcome of ARDS • Mortality rate approximately 60% • deaths attributable to sepsis or multiorgan failure or direct lung injury • improvements in therapy for sepsis, mechanical ventilation and supportive care has reduced mortality two approximately 40% in US. • Survivors may have persistent impairment. 55 Activated macrophage and hypertrophic / hyperplasia pneumocyte 2 also leads to fibrosis 56 Obstructive Pulmonary Disease • Characterized by a limitation of airflow • Due to increase in resistance in airflow: caused by partial or complete obstruction at any level from trachea to bronchioles • Characterized by a decreased expiratory rate, although total lung capacity can be either normal or increased. • May result from: • Anatomic airway narrowing (asthma) • Loss of elastic recoil (emphysema) • The major diffuse obstructive disorders are: • emphysema ] • chronic bronchitis ] • asthma and • bronchiectasis COPD Figure 12‐05. Schematic representation of overlap between chronic obstructive lung diseases 57 19 10/6/2023 Emphysema • Condition of lung • irreversible enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their (e.g. alveolar) walls without fibrosis • Characterized by mild chronic inflammation • epithelium and macrophages release leukotriene B4, TNF, IL‐8 • Macrophages, CD8+ & CD4+ T lymphocytes • Recruitment of neutrophils • Destruction of connective tissue a consequence of imbalance of protease‐antiprotease and oxidative stress • Neutrophils are principal source of proteases • Inflammatory cells produce ROS • Clear association between heavy cigarette smoking and emphysema 58 Figure 12‐08. Pulmonary emphysema. There is marked enlargement of air spaces, with destruction of alveolar septa but without fibrosis. Note presence of black anthracene pigment. Figure 12‐09. Bullous emphysema with large apical and subpleural bullae. (From the Teaching Collection of the Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.) 59 Asthma • Chronic inflammatory disorder of the conducting airways that causes recurrent episodes of wheezing, breathlessness, chest tightness and cough • Characterized by • reversible and intermittent bronchoconstriction caused by airway sensitivity to variety of stimuli / allergens • chronic bronchial inflammation • increased mucus production • Between attacks, patients may be virtually asymptomatic Two major types: • Atopic • Evidence of allergen sensitization and immune activation • Type I hypersensitivity • Non‐atopic ‐ No evidence of allergen sensitization 60 20 10/6/2023 Non‐atopic (intrinsic) asthma: triggered by non‐immune stimuli such as aspirin, pulmonary infections (virus), cold, physiologic stress, exercise and inhaled air pollutants e.g. cigarette smoke Atopic (extrinsic) asthma: genetic predisposition to type I hypersensitivity • immune response to environmental allergens • T cells (Th2) and their mediators promote inflammation and stimulate B cells: • IL‐4 ‐ stimulates IgE production • IL‐5 ‐ activates eosinophils • IL‐13 ‐ stimulates mucus production 61 Atopic (extrinsic) asthma: smooth muscle contraction • Acute (immediate) phase: pre‐formed inflammatory mediators, mast cells. • Bronchoconstriction – parasympathetic stimulation, central + local, triggered by mediators • Increased mucus production • Vasodila on + ↑ permeability • Late (4‐8 h later) phase : • more inflammatory cell infiltration: eosinophils, neutrophils and T cells (Th2 + Th17) • synthesis of cellular mediators • leukotrienes C4, D4, E4 (prolong bronchoconstric on, ↑ permeability+ mucus production) • Acetylcholine release • Histamine, PGD2, PAF • Others 62 63 21 10/6/2023 Clinical Outcomes • "Attacks" last up to several hours. The paroxysm may persists for day or even weeks. • May be fatal. • Acute airway obstruction due to bronchoconstriction, acute edema and mucus plugging • occlusion of bronchi and bronchioles by thick, tenacious mucus plugs • Over distention of lungs In chronic asthma • Thickening of airway wall, sub basement membrane fibrosis (type I and type III collagen) • hypertrophy of submucosal glands and increased number of airway goblet cells • hypertrophy and/or hyperplasia of the bronchial wallssmooth muscle. 64 Pneumonia • Pneumonia is inflammation of the lung parenchyma characterized by consolidation of the affected part, e.g. alveolar spaces filled with exudate • Pneumonitis refers to inflammation of the lung generally involving the alveolar interstitium and without exudate in the alveoli • Classification according to a variety of different features • Presumed cause • e.g. viral, verminous • Type of inflammatory exudate • e.g. suppurative, fibrinous, granulomatous • Morphologic features • e.g. embolic, proliferative • Distribution of lesions, • e.g. cranioventral, diffuse, lobar • Attributes of the pneumonic process • e.g. enzootic, contagious, atypical 65 • Two of the anatomic or radiographic patterns of pneumonia: • Bronchopneumonia: patchy consolidation involving more than one lobe (initial infection of bronchi with extension to alveoli) • Lobar pneumonia: regional consolidation –contiguous spaces of part or all of a lobe filled with exudate Morphology of lobar pneumonia: evolves through 4 stages: (1) congestion, (2) red hepatization, (3) grey hepatization, (4) resolution 66 22 10/6/2023 67 68 69 23 10/6/2023 Further classifications of pneumonia • Bronchopneumonia • Refers to pneumonia in which inflammatory process occurs in the bronchial, bronchiolar, and alveolar lumens • exudate collects in the bronchial, bronchiolar and alveolar lumina leading to conslidation • Most common type in domestic animals • Characterized by a cranioventral consolidation of the lungs • Comparable to anteriosuperior in human anatomy • Caused by viruses bacteria, mycoplasmas, aspiration • Route of entry of injurious agents (e.g. bacteria) causing bronchopneumonia is via the inspired air, i.e. aerogenous. • Source is aerosolized droplets containing infectious particles or from the nasal flora 70 Fig. 9‐56A Suppurative bronchopneumonia, enzootic pneumonia, lung, calf. A, Cranioventral consolidation (C) of the lung involves approximately 40% of pulmonary parenchyma. Most of the caudal lung is normal (N). B, Cut surface. Consolidated lung is dark red to mahogany (C), and a major bronchus contains purulent exudate (arrow). N, Normal. (A courtesy Dr. A. López, Atlantic Veterinary College. B courtesy Ontario Veterinary College.) 71 Fig. 9‐58A Fibrinous bronchopneumonia (pleuropneumonia), right lung, steer. A, The pneumonia has a cranioventral distribution that extends into the middle and caudal lobes and affects approximately 80% of the lung parenchyma. The lung is firm, swollen, and covered with yellow fibrin (*). The dorsal portion of the caudal lung is normal (N). B, Cut surface. Affected parenchyma appears dark and hyperemic as compared with more normal lung (top quarter of figure). Interlobular septa are prominent (yellow bands) due to the accumulation of fibrin and edema fluid. This type of lesion is typical of Mannheimia haemolytica infection in cattle (shipping fever). (A courtesy Ontario Veterinary College. B courtesy Dr. A. López, Atlantic Veterinary College.) 72 24 10/6/2023 Fig. 9‐72A Pneumonic Mannheimiosis (Mannheimia haemolytica), lung, steer. A, Cut surface. Interlobular septa (arrowheads) are notably distended by edema and fibrin. In the lung parenchyma are irregular areas of coagulative necrosis (arrows) surrounded by a rim of inflammatory cells. C, Note alveoli filled with fibrin (asterisks) and with neutrophils (N). The interlobular septa (IS) is distended with proteinaceous fluid. H&E stain. (A, B, and C courtesy Dr. A. López, Atlantic Veterinary College. D courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) 73 Atypical pneumonia • Characterized by respiratory distress disproportionate to clinical and radiologic signs, and by inflammation that is confined to alveolar septae, i.e. alveoli devoid of exudate • Most common cause in humans is Mycoplasma pneumoniae. • Other causes: intracellular bacteria (chlamydia), viruses (influenza A & B, severe acute respiratory syndrome (SARS), Coxiella burnetti (Q fever) Pathogenesis: microbial a achment to epithelium → cell necrosis → inflammation within alveolar walls (interstitial), type II pneumocyte hypertrophy  Predisposition to secondary bacterial infection 74 Further classifications of pneumonia • Interstitial pneumonia • Refers to pneumonia in which the inflammatory process is localized to the components of the alveolar walls, i.e. the endothelium, basement membrane and alveolar epithelium (pneumocytes) and the contiguous bronchiolar interstitium • Can be the consequence of injury to pneumocytes from aerogenously delivered agents, or from injury to alveolar capillary endothelium or basement membrane from hematogenously delivered agents • Aerogenous agents include inhaled toxic gases or inhaled pneumotropic viruses (e.g. influenza) • Hematogenous agents include bacterial toxins (sepsis, endotoxemia), endotheliotropic viruses • Injury to type I pneumocytes or capillary endothelium disrupts blood‐air barrier and leads to an acute exudative reaction that includes neutrophil infiltration of alveolar interstitium…characterizes acute interstitial pneumonia • Persistent injury leads to fibrosis of alveolar walls, infiltration by macrophages, lymphocytes,fibroblasts, and proliferation of type II pneumocytes…characterizes chronic interstitial pneumonia 75 25 10/6/2023 Fig. 9‐60A Interstitial pneumonia, lung, feeder pig. A, The lung is heavy, pale, and rubbery in texture. It also has prominent costal (rib) imprints (arrows), a result of hypercellularity of the interstitium and the failure of the lungs to collapse when the thorax was opened. B, Transverse section. The pulmonary parenchyma has a “meaty” appearance and some edema, but no exudate is present in airways or on the pleural surface. This type of lung change in pigs is highly suggestive of a viral pneumonia. (Courtesy Dr. A. López, Atlantic Veterinary College.) 76 Fig. 9‐61A Interstitial pneumonia, lung, aged ewe. A, The alveolar septa are notably thickened by severe interstitial infiltration of inflammatory cells. H&E stain. B, Higher magnification view of A showing large numbers of lymphocytes and other mononuclear cells infiltrating the alveolar septal interstitium. H&E stain. (A courtesy Western College of Veterinary Medicine. B courtesy of Dr. A. López, Atlantic Veterinary College.) 77 Further classifications of pneumonia • Embolic pneumonia • Refers to pneumonia in which the inflammatory process is centered on blood vessels because the injurious agent is hematogenously delivered to the lung from a site of infection outside the lung • Inflammatory response is typically centered on pulmonary arterioles and alveolar capillaries (small diameter blood vessels) • Requires that circulating bacteria or fungi attach to pulmonary endothelium AND evade phagocytosis by pulmonary intravascular macrophages or neutrophils • Characterized by multifocal lesions randomly distributed in the lobes of the lungs • Sources of septic emboli include hepatic abscesses (which rupture into the caudal vena cava), omphalophlebitis, chronic bacterial or fungal skin, mouth (or hoof) infections, and contaminated intravascular catheters • Agents include Streptococcus spp. Staphylococcus spp, and other bacteria, as well as fungi, e.g. Aspergillus spp. 78 26 10/6/2023 Fig. 9‐63 Embolic pneumonia, lungs, 6‐week‐old puppy. Large hemorrhagic foci are scattered relatively uniformly throughout all pulmonary lobes (arrows). These hemorrhagic foci are the sites of lodgment of Pseudomonas aeruginosa emboli (septic) that originated from necrotizing enteritis. Note the multifocal distribution of the inflammatory foci, which is typical of embolic pneumonia. Septic emboli were also present in the liver. (Courtesy Atlantic Veterinary College.) 79 Fig. 9‐64A Embolic pneumonia, lung, cow. A, Foci of necrosis and infiltration of neutrophils (arrows) resulting from septic emboli. Note the multifocal distribution of the lesion, which is typical of embolic pneumonia. Vegetative endocarditis involving the tricuspid valve was the source of septic emboli in this cow. H&E stain. B, Embolic focus in the lung. Note bacterial colonies (arrows) mixed with neutrophils and cellular debris. H&E stain. (Courtesy Dr. A. López, Atlantic Veterinary College.) 80 Further classifications of pneumonia • Granulomatous pneumonia • Refers to pneumonia in which the injurious agent evokes a granulomatous inflammatory response • Injurious agent can be delivered to the lung aerogenously or hematogenously • Granulomatous pneumonia can share portals of entry or sites of initial injury with other types of pneumonias, e.g. interstitial or embolic…unique quality of granulomatous pneumonias is the inflammatory response • Characterized by activation of alveolar and interstitial macrophages together with lymphocytes (CD4 T cells), and can involve neutrophils and multinucleate giant cells • Most common causes include systemic fungal diseases, e.g. cryptococcosis, coccidioidomycosis, histoplasmosis, blastomycosis…and also by bacteria, particularly mycobacteria • Entry is typically via the aerogenous route 81 27 10/6/2023 Fig. 9‐65B Pulmonary tuberculosis, lung, aged cow. A, Multifocal, coalescing granulomatous pneumonia involves most of the lung, except for the dorsal portion of the caudal lung lobe. B, Transverse section. Large multifocal to confluent caseating granulomas are present in the pulmonary parenchyma. Note the caseous (“cheesy,” pale yellow‐white) appearance of the granulomas, which is typical of bovine tuberculosis. (A courtesy Facultad de Medicina Veterinaria y Zootecnia, UNAM, México. B courtesy Dr. J.M. King, College of Veterinary Medicine, Cornell University.) Fig. 9‐66 Granulomatous pneumonia, lung, cow. There are several noncaseous granulomas (arrows), each with a small necrotic center filled with neutrophils, surrounded by histiocytes and mononuclear cells, and with an outer rim of connective tissue. H&E stain. (Courtesy Western College of Veterinary Medicine.) 82 Fig. 9‐67A Granulomatous pneumonia (Rhodococcus equi), lungs, foal. A, Cranioventral consolidation of the lungs with subpleural granulomas. Note that the pneumonic lesions in this foal are unilateral. This was an experimental case in which a foal was intratracheally inoculated with a suspension of Rhodococcus equi. B, Cut surface. Note the large, confluent, caseated granulomas. (Courtesy Drs. J. Yager and J. Prescott, Ontario Veterinary College.) 83 Pleural Lesions • Pleural effusion is the presence of fluid in pleural space, and it can be transudate or exudate • Effusion that is transudate is hydrothorax • Causes of pleural exudate: microbial invasion (pleuritis/empyema), cancer, pulmonary infarction, viral pleuritis • Pneumothorax refers to air or gas in pleural sac; spontaneous or secondary to thoracic/lung disorder. ‐ Consequences: tension, compromise of pulmonary circulation, lung collapse, infection • Hemothorax is the collection of blood in pleural cavity due to ruptured aortic aneurysm • Chylothorax is pleural collection of milky lymphatic fluid containing microglobules of lipid, and implies obstruction of major lymph ducts • Pyothorax is the collection of pus in the pleural cavity due to infection by pyogenic bacteria 84 28 10/6/2023 Fig. 9‐100 Hemothorax, right pleural cavity, dog. The right pleural cavity is filled with a large clot of blood from a ruptured thoracic aortic aneurysm, which caused unexpected death. Canine aortic aneurysms are associated with migration of Spirocerca lupi larvae along the aortic wall before their final migration into the wall of the adjacent esophagus. In other cases like this dog, the cause remains unknown (idiopathic aortic aneurysm). (Courtesy Dr. L. Gabor and Dr. A. López, Atlantic Veterinary College.) 85 Fig. 9‐101 Chylothorax (cause unknown), thoracic (pleural) cavity, mink. Lymph (chyle) fills both the left and right pleural cavities. The heart (H) and pericardium are essentially normal because the chyle does not adhere to the outer surface of the pericardial sac, as typically happens with suppurative and fibrinous exudates in the thoracic cavity. (Courtesy Western College of Veterinary Medicine.) 86 Fig. 9‐102 Pyothorax (Pasteurella multocida), right pleural cavity, cat. Pus in the thoracic cavity is called pyothorax or empyema. Purulent exudate also covers the visceral and parietal pleurae. This lesion is also referred to as suppurative pleuritis. (Courtesy Dr. A. López, Atlantic Veterinary College.) 87 29 10/4/2023 Pathogenesis of ARDS acute injury to the alveolar epithelium and capillary endothelium → increasing inflammation and pulmonary damage • Endothelial activation ‐ dt pneumocyte damage or circulating inflammatory mediators • Neutrophils and their products play a crucial role (ROS, proteases, platelet‐activating factor, leukotrienes) • MIF 55 Histopathology of ARDS Early (exudative) stage: edema, epithelial necrosis, accumulation of neutrophils, hemorrhage, and hyaline membranes, which consist of inspissating protein/fibrin‐rich edema fluid admixed with remnants of necrotic alveolar epithelial cells Organizing stage: marked proliferation of type II pneumocytes; resorption of the hyaline membranes and thickening of the alveolar septa by inflammatory cells, fibroblasts and collagen Figure 13‐3A. Diffuse alveolar damage in acute lung injury and acute respiratory distress syndrome. Some alveoli are collapsed; others are distended. Many are lined by bright pink hyaline membranes (arrow). B, The healing stage is marked by resorption of hyaline membranes with thickening of alveolar septa containing inflammatory cells, fibroblasts, and collagen. Numerous reactive type II pneumocytes also are seen at this stage (arrows), associated with regeneration and repair. A, 56 Outcome of ARDS • Mortality rate approximately 60% • deaths attributable to sepsis or multiorgan failure or direct lung injury • improvements in therapy for sepsis, mechanical ventilation and supportive care has reduced mortality two approximately 40% in US. • Survivors may have persistent impairment. 57 19