Chemical Mediators PDF

Chemical Mediators, Types with Clinical Examples of Acute Inflammation Prof Dr Thidar Aung Learning Objectives Students will be able to: 1. State the plasma-derived and cell-derived chemical mediators and describe their role in inflammation. 2. Describe the special macroscopic appearances in acute i...

Chemical Mediators, Types with Clinical Examples of Acute Inflammation Prof Dr Thidar Aung Learning Objectives Students will be able to: 1. State the plasma-derived and cell-derived chemical mediators and describe their role in inflammation. 2. Describe the special macroscopic appearances in acute inflammation. Chemical Mediators of Inflammation Plasma-derived: Circulating precursors Have to be activated Cell-derived: Sequestered intracellularly Synthesized de novo Mediators are tightly regulated Cell-Derived Mediators 1. Vasoactive Amines: Histamine: Found in mast cells, basophils, and platelets Promotes arteriolar dilation and venular endothelial contraction Results in widening of inter-endothelial cell junctions with increased vascular permeability Serotonin: Vasoactive effects similar to histamine Found in platelets Released when platelets aggregate 2. Phospholipid-Derived Products: Arachidonic Acid (AA) Metabolites: A component of cell membrane phospholipids Occurs via two major pathways: Lipoxygenase: Produces HETE, PETE, Leukotrienes Increases permeability, causes vasospasm, bronchospasm Cyclooxygenase: Produces Prostaglandins (causing edema, pain), Prostacyclins (vasodilation, inhibits platelet aggregation), and TXA2 (vasoconstriction, promotes platelet aggregation) Platelet Activating Factor (PAF): Produced by endothelial cells and immune cells Induces aggregation of platelets, increases vascular permeability, enhances leukocyte adhesion, chemotaxis, degranulation, and oxidative burst 3. Reactive Oxygen Species (ROS): Eliminate bacteria Cause tissue damage, direct injury to endothelial cells, injury to extracellular matrix, and other cell types (e.g., tumor cells) 4. Nitric Oxide: Toxic to bacteria Causes vasodilation Contributes to tissue damage 5. Cytokines and Chemokines: Include TNFα, IL1, IL6, IL17 Short-acting soluble mediators Produced mainly by resident and recruited macrophages, but also by other cells Multifunctional Act as danger signals Activation of self (autocrine), recruited cells, endothelial cells Cause changes in morphology and adhesive properties of endothelial cells Induce systemic effects (fever, increased acute phase proteins) Secreted by lymphocytes (lymphokines), macrophages/monocytes (monokines) Act between cells of the immune system (interleukins) Induce chemotaxis of leukocytes (chemokines such as CXCL-8/IL8, MCP-1) 6. Neuropeptides: Secreted by sensory nerves and various leukocytes Play a role in the initiation and regulation of inflammatory responses Substance P and neurokinin A are produced in the central and peripheral nervous systems Nerve fibers containing Substance P are prominent in the lung and gastrointestinal tract Plasma-Derived Mediators 1. Plasma Proteases: Complement System: Plasma contains over 20 proteins that circulate in the blood: complement (C) proteins These proteins ‘complement’ antibody action Synthesized in the liver Inactive until activated by recognizing bacteria/pathogens Cleaved by a protease to an active form Once activated, they cleave and activate another part of the cascade Complement Activation: Classical Pathway: Triggered by formation of the antibody-antigen complex Alternative Pathway: Complement binds to pathogen surface, tagging it for destruction Lectin Pathway: Plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1 Role of Complement: Inflammation: (C3a and C5a) C3a, C5a = anaphylotoxins Vascular effects: Increase vascular permeability and vasodilation Cellular effects: Leukocyte activation, adhesion, and chemotaxis (C5a) Immunity: (C5-9 complex) (Membrane Attack Complex/ MAC C5-9) Punches a hole in the membrane Kinin System: Leads to formation of bradykinin Bradykinin causes: Increased vascular permeability Arteriolar dilation Smooth muscle contraction Pain Bradykinin is short-lived (kininases) Clotting System: Key to activation is factor XII The end result is fibrin formation Special Macroscopic Appearances in Acute Inflammation 1. Serous Inflammation: Result from the exudation of cell-poor fluid (serous) from plasma or secretions of mesothelial cells lining the peritoneum, pleura, or pericardium cavities (effusion) The fluid does not contain microbes or large numbers of leukocytes Examples: skin blister resulting from a burn or viral infection, peritonitis, synovitis 2. Fibrinous Inflammation: Increased vascular permeability allows fibrinogen to pass out, forming fibrin, which is deposited in the extracellular space Examples: fibrinous pericarditis, meningitis, pleuritis Fibrinous exudates are dissolved by fibrinolysis and cleared by macrophages If not removed, fibroblasts and blood vessels grow into the area, causing scarring Conversion of the fibrinous exudate to scar tissue (organization) can lead to opaque fibrous thickening of the pericardium and epicardium, possibly obliterating the pericardial space 3. Purulent (Suppurative) Inflammation and Abscess: Characterized by the production of pus consisting of neutrophils, liquefied debris of necrotic cells, and edema fluid Most frequent cause is infection with pyogenic (pus-producing) bacteria, such as staphylococci Examples: acute appendicitis, bronchopneumonia Can cause liquefactive necrosis Abscesses are localized collections of pus with a central region of necrotic tissue surrounded by neutrophils, congested vessels, and fibroblasts Abscesses may be walled off and replaced by connective tissue 4. Ulcer: A local defect or excavation of the surface of an organ or tissue caused by sloughing (shedding) of inflamed necrotic tissue Occurs when tissue necrosis and resultant inflammation exist on or near a surface Most common in: The mucosa of the mouth, stomach, intestines, or genitourinary tract (e.g., peptic ulcer) The skin and subcutaneous tissue of the lower extremities (e.g., diabetic ulcer) 5. Others: Catarrhal Inflammation: Inflammation of mucous membranes marked by secretion of mucus (e.g., rhinitis in common cold) Pseudomembranous Inflammation: Severe injury associated with extensive epithelial necrosis and sloughing, creating large shallow ulcers covered by a white or cream-colored false membrane (e.g., diphtheria, pseudomembranous colitis)