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23 Cards in this Set
- Front
- Back
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What reduces airway caliber and increases resistance?
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Changes in lumen
-Increased secretions (asthma, bronchitis, COPD, CF) Airway wall thickening and/or constriction -Inflammation (asthma and chronic bronchitis) -bronchial smooth muscle contraction (asthma) Supporting structures -Emphysema with supporting elastic tissue destruction and expiratory airway collapse (COPD) |
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Acute asthmatic inflammation: Triggers
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Extrinsic (type I hypersensitivity reaction to extrinsic antigens
Intrinsic – nonimmune triggers (aspirin, infections, cold, stress, exercise, irritants) CD4+ Th2 cells mediate extrinsic -Secrete IL-4 and IL-5 which stimulate IgE synthesis, mast cell and eosinophil growth and activation |
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Acute asthmatic inflammation: early and late phase
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Early phase is ~ 30-60 minutes – attack on mucosal lining with some denudation of epithelium
Afferent neurons stimulated (vagal) - Increased (exaggerated) airway reactivity – reversible bronchospasms to stimuli Increased mediator production – lipid mediators include: Leukotrienes C4, D4 E4, Prostaglandin E2, LTB4, PAF Result is bronchoconstriction, edema and mucus secretion Late phase is ~ 4-8 hours – leukocyte dominated via increased adhesion to vascular endothelium |
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Leukocyte immigration into lung
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Rolling:
-P and E selectins initiate rolling Integrins on leukocyte activated by chemokines Integrins bind to integrin ligands (ICAM-1) Cell migrates through endothelium |
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Asthmatic inflammation: Chronic changes
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Epithelial, macrophages and other cells produce TGF-b, TGF –m, and fibroblast growth factors as drivers of chronic inflammation
Pathology reveals: -Increased inflammatory cell numbers in submucosa, eosinophils -Subepithelial myofibroblasts proliferate and produce increased interstitial collagen - submucosal fibrosis – appears as thicker basement membrane -Smooth muscle hypertrophy/hyperplasia in bronchial walls -Secretory gland hyperplasia – can be significant mucous plugging – especially in severe, fatal asthma Tissue outcomes: -Diffuse obstruction with scattered perfusion-ventilation mismatching (not pure shunting) -CO2 can be normal or low but hypercapnia is an ominous sign |
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COPD Pathogenesis
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Functionally, persistent airflow obstruction
-chronic and poorly reversible A significant pulmonary disease in the US, 2-4th rank for morbidity and mortality History of smoking is prevalent Functional definition via pulmonary function testing (↓FEV1:FVC) Associated with two distinct pathologies - emphysema (acinar level) and chronic bronchitis (bronchial level) Emphysema is permanent enlargement of airspaces distal to terminal bronchioles -It is a morphologic definition resulting from destruction of alveolar walls with obvious fibrosis -Not simple overinflation where air space morphology is stretched but intact Chronic bronchitis -A clinical definition -Persistent increased bronchial mucus secretion -Chronic productive cough |
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COPD Airway pathology: emphysema
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Emphysema morphology
Defined by enlarged airspace due to destruction of supporting wall structure -Inflammation and irritation increases neutrophils which generate elastase and other proteases -Decrease in alpha1-antitrypsin (alpha1-AT usually breaks down elastase and other proteases) Centriacinar – often smokers, chronic inflammation, dark deposits Panacinar – often lower lobes and often associated with a1-AT Inactivation imbalance of a1AT allows tissue damage via destruction of elastic tissue surrounding distal airways and alveloi Can be centriacinar in patients with normal a1AT Decreased gas exhange |
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Eicosanoid derivatives
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Products of arachidonic acid
Leukotrienes (LT) – primarily in inflammatory cells Prostaglandins (PG) – most all cells Thromboxanes (TX) – primarily platelets Lipoxins (LX) – primarily transcellular, involving neutrophils cooperating with other cell types Potent (nanomolar) Act in a paracrine or autocrine manner Act via binding to G-protein-coupled receptors |
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COPD cellular and molecular mechanisms
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Protease- antiprotease mechanism
Chronic inflammation -Increases neutrophil elastase -Inactivation of alpha1-AT (functional deficiency) Macrophages, CD8+ and CD4+ T lymphocytes, and neutrophils Signaling - nicotine and ROS activation of neutrophils NFkB activated to increase TNF and IL-8 which sustains neturophils, major cellular player, degranulation releases elastase, cathepsin G, proteinase 3 Macrophages produce elastase and metaloproteinases also key, not inhibitied by a1AT ROS imbalance from smoke and neutrophils also contributes to depletion of cellular antioxidants GSH, SOD and directly injures cells and a1AT |
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Airway obstruction from emphysema
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Small airways normally tethered by elastic recoil of the lung parenchyma
Loss of elastic tissue in the walls that surround respiratory bronchioles Reduces “radial traction” - respiratory bronchioles collapse during expiration Creates functional airflow obstruction despite the absence of mechanical obstruction |
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Chronic bronchitis: mechanism
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Spectrum from simple to mucopurulent to having components of asthma to obstructive disease
Cigarette smoke, irritants and pollutants (SO2, NO2) induce neurohumoral pathways Distinctive feature is hypersecretion of bronchial mucous glands – begins early Hypertrophy of sub-mucousal glands - size increase key observation Neutrophils activated to secrete elastase, cathepsin and metaloproteinases further stimulate mucous hypersecretion Metaplastic formation of mucin-secreting goblet cells in bronchial surface epithelium (protective response to irritant?) Microbial infections complicate secondary picture |
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COPD cellular pathology: chronic bronchitis
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Hypertrophy of bronchial wall mucous glands associated with chronic inflammation
Ratio of mucous gland thickness to bronchial wall thickness is increased Fibrous replacement of the muscular walls of small bronchioles Fibrotic bronchioles tend to collapse in expiration |
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Cytokine overview
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Cytokines large group of proteins, peptides or glycoproteins secreted by specific cells of immune system.
- signaling molecules that mediate and regulate immunity, inflammation and hematopoiesis - Includes over 100 gene products - interferons, interleukins (~33), chemokine family, mesenchymal growth factors, tumor necrosis factor family (~20) and adipokines - produced throughout the body by cells of diverse embryological origin. Example cytokines made by lymphocytes are lymphokines Interleukins made by one leukocyte - act on other leukocytes Chemokines - cytokines with chemotactic activity Adipokines – adipose tissue, including macrophages in that tissue Cytokines may act: - on the cells that secrete them (autocrine action) - on nearby cells (paracrine action) - on distant cells (endocrine action) |
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Cytokine functions
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lymphocyte growth factors,
pro-inflammatory anti-inflammatory polarize the immune response to antigen Orchestrate energy/metabolic (fat/insulin) responsiveness Auto-immune vs auto inflammatory -Innate response is required for host survival --IFNg defends against intracellular pathogens M tuberculosis -but is also causative in auto-immune disease -IL- 2 yields cytotoxic T- cells, but mediates graft vs host disease POTENT – 10 pM IL-1 induces COX-2 |
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Challenges in cytokine therapeutics
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Overlapping biology
Cytokines required for immunity, but not necessarily visible function until body is challenged Mouse ≠ human -Molecules have some differences, disease models fail to always translate, knock-out mice often develop normally until challenged Successful history -G-CSF or GM-CSF - bone marrow suppression associated with radiation, chemotherapy or transplantation; GM-CSF - Crohn’s Disease -Erythropoietin (EPO) is routinely used with anemia and bone marrow failure -IFNα is administered to treat hepatitis B and C; IFNβ multiple sclerosis -Monoclonal antibodies against TNFa or TNF receptors successful in RA, Crohn's, and psoriasis |
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Lipid mediators of inflammation
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Arachidonic acid is freed from a membrane phospholipid molecule by the enzyme phospholipase A2
AA is a precursor in the production of eicosanoids The enzymes cyclooxygenase and peroxidase lead to prostaglandin H2 which in turn is used to produce the prostaglandins, prostacyclins, and thromboxanes The enzyme 5-lipoxygenase leads to 5-HPETE which in turn is used to produce the leukotrienes Cytochrome p450 converts AA to HETE and poxygenase converts HETE to EETs |
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Actions of leukotrienes
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LTB4 exits cell via LTB4 transporter
Binds to G protein coupled receptor in neutrophils and other tissues LTB4 in airways is chemoattractive to neutrophils LTC4 exits cell via multidrug resistance-associated protein (MRP1) Is metabolized to LTD4 LTD4 acts on receptors in airway smooth muscle cells and postcapillary venule endothelial cells to cause bronchoconstriction and edema. |
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Actions of prostaglandins
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AA released from membrane lipids and metabolized by COX1 or COX2 to intermediate PGH2.
Depending on what cell type, different PGH2 metabolizing enzymes can form PGE2, PGD2, PGF2alpha, PGI2 (prostacyclin), and TxA2 (Thromboxane) Prostaglandins undergo facilitated transport from cell through a transporter to exert autocrine or paracrine actions on a family of PG receptors Thromboxane (platelets): -Vasoconstriction -Aggregation Prostacyclin -Vasodilation -Declumping PGF2alpha -Contraction, parturition (uterine smooth muscle) PGD2 -Chemotaxis (Th2 lymphocyte) -Allergic asthma (lung epithelial cell) PGE2 -Bone resorption (osteoclast) -Fever (brain) -Ovulation and fertilization (Ovary) -Pain response (spinal neurons) |
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Chronic bronchitis: Anatomic site, major pathologic changes, etiology, signs and symptoms
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Anatomic site:
Bronchus Pathology Mucous gland hyperplasia and hypersecretion Etiology Tobacco smoke Air pollutants Signs/symptoms Cough Sputum production |
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Bronchiectasis: Anatomic site, major pathologic changes, etiology, signs and symptoms
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Anatomic site:
Bronchus Pathology Airway dilation and scarring Etiology Persistent or severe infections Signs/symptoms Cough, purulent sputum, fever |
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Asthma: Anatomic site, major pathologic changes, etiology, signs and symptoms
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Anatomic site:
Bronchus Pathology Smooth muscle hyperplasia, excess mucus, inflammation Etiology Immunological or undefined causes Signs/symptoms Episodic wheezing, cough, dyspnea |
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Emphysema: Anatomic site, major pathologic changes, etiology, signs and symptoms
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Anatomic site:
Acinus Pathology Airspace enlargement, wall destruction Etiology Tobacco smoke Signs/symptoms Dyspnea |
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Small airway disease, bornchiolitis: Anatomic site, major pathologic changes, etiology, signs and symptoms
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Anatomic site:
Bronchiole Pathology Inflammation, scarring/obliteration Etiology Tobacco smoke, air pollutants, miscellaneous Signs/symptoms Cough, dyspnea |
