Download The Cell-Derived Mediators of Chemical Mediators of Inflammation

The Cell-Derived Mediators of Chemical Mediators of Inflammation Presented by Sara M. Al-Shaker Wed. 5/11/2008 King Saud University Riyadh, KSA

Introduction • What are mediators? A mediator is a substance or structure that mediates a specific response in a bodily tissue

General Properties of Chemical Mediators of Inflammation • Site of production Local or remote • Method of action  Mostly by binding to receptors  May have direct enzymatic and/or toxic effects

General Properties of Chemical Mediators of Inflammation • Some mediators Stimulate release of secondary effector molecules • Actions of most mediators are tightly regulated Decay Enzymatic inactivation Elimination Inhibition

Chemical Mediators of Inflammation

Cell-Derived

Plasma-ProteinDerived

Chemical Mediators of Inflammation

Cell-Derived

Plasma-Protein-Derived Vasoactive Amines

Eicosanoids PAF Cytokines Chemokines ROS NO Lysosomal Enzymes of Leukocytes Neuropeptides

Chemical Mediators of Inflammation

Cell-Derived

Plasma-ProteinDerived

Complement

Coagulation and Kinin Systems

Cell-Derived Mediators • Producing cells: 

Tissue macrophages  Mast cells  Endothelial cells  Leukocytes

Vasoactive Amines Histamine & Serotonin

Vasoactive Amines • Among first mediators in acute inflammatory reactions • Preformed mediators in secretory granules

Histamine •

•

Source: many cell types, esp. mast cells, circulating basophils, and platelets Actions:

ARTERIOLAR DILATION INCREASED VASCULAR PERMEABILITY  ENDOTHELIAL ACTIVATION 



•

Inactivated by:

Histaminase

Histamine • 1. 2. 3.

Stimuli of Release: Physical injury Immune reactions C3a and C5a fragments of complement (anaphylatoxins) 4. Leukocyte-derived histamine-releasing proteins 5. Neuropeptides (e.g. substance P) 6. Certain Cytokines (e.g. IL-1 and IL-8)

Serotonin (5-HT) • Source: Platelets • Action:

Similar to histamine’s • Stimulus: Platelet aggregation

Eicosanoids Eicosanoids = Arachidonic Acid (AA) Metabolites = Prostaglandins (PG), Leukotrienes, and Lipoxins

Eicosanoids •

May be thought of as hormones but they differ from hormones by: 1. Produced in all tissues rather than in specialized glands 2. Act locally rather than after transport in blood to distant sites

• •

Decay spontaneously OR enzymatically Have short half-life

Eicosanoids • Source: Leukocytes Mast cells Endothelial cells Platelets

Arachidonic Acid • 20-carbon polyunsaturated fatty acid (4 double bonds) • Obtained from dietary linoleic acid • Present in the body in its esterified form as a component of cell membrane phospholipids • Released from phospholipids via phospholipases

AA Metabolism •

Two major enzymatic pathways: 1. Cyclooxygenase  Prostaglandins & Thromboxanes 2. Lipooxygenase  Leukotrienes and Lipoxins

Chemical Mediators of Inflammation

Cell-Derived

Plasma-Protein-Derived Vasoactive Amines

Eicosanoids PAF Cytokines Chemokines ROS NO Lysosomal Enzymes of Leukocytes Neuropeptides

Platelet Activating Factor (PAF) • Another phospholipid derivative • Very potent bioactive molecule • Source: membranes of Neutrophils, monocytes, basophils, endothelial cells, & platelets • Derived by the action of Phospholipase A2 • Acts via G-protein-coupled receptor

PAF • Actions:  Platelet activation (aggregation & degranulation)  Vasoconstriction  Bronchoconstriction  Leukocyte adhesion  Leukocyte degranulation  Chemotaxis  Synthesis of other mediators, esp. Eicosanoids

Cytokines • Polypeptides • Actions:  Involved in early immune and inflammatory reactions  Some stimulate bone marrow precursors to produce more leukocytes

Cytokines • • • •

Interleukins (IL) Tumor Necrosis Factor (TNF) Chemokines Interferon-γ (INF- γ)

Acute inflammation: IL-1, TNF, & chemokines Chronic Inflammation: INF- γ & IL-12

TNF and IL-1 • Source:

Activated macrophages Mast cells Endothelial cells • Stimulation: Bacterial endotoxins Immune complexes Products of T-lymphocytes (adaptive immune response)

TNF and IL-1 • Actions:

Endothelial Activation

Both: 1. Stimulate expression of molec. on endothelial cells  2. Increased leukocyte binding and recruitment 3. Enhanced production of additional cytokines (notably chemokines) and eicosanoids

TNF and IL-1 • Actions:

TNF : • Thrombogenicity of endothelium • Neutrophil activation IL-1: • Tissue fibroblasts activation  increased ECM N.B. TNF and IL-1 may enter the circulation and induce systemic acute-phase reaction

Chemokines • •

Small proteins They are chemoattractants for leukocytes • Main functions: 1. Leukocyte recruitment & activation in inflammation 2. Normal anatomic organization of cells in lymphoid and other tissues • Act via G-protein-coupled receptors (e.g. CXCR4 and CCR5 important for HIV entry into lymphocytes)

Reactive Oxygen Species • Synthesized via NADPH oxidase pathway • Source: Neutrophils and Macrophages • Stimuli of release: Microbes Immune complexes Cytokines

Nitric Oxide • • • • 1.

Short-lived SOLUBLE Free-radical gas Isoforms of NO Synthase (NOS): Type I (nNOS) : neuronal, not significant in inflammation 2. Type II (iNOS): inducible, in macrophages and endothelial cells, NO production in inflammation 3. Type III (eNOS): constitutive, endothelium

NO • Functions: 1. Vasodilation 2. Antagonism of platelet activation (adhesion, aggregation, & degranulation) 3. Reduction of leukocyte recruitment 4. Microbicidial (cytotoxic) agent (with or without ROS) in activated macrophages

Lysosomal Enzymes of Leukocytes Leukocytes: Neutrophils & Monocytes Enzymes: • Acid proteases • Neutral proteases (e.g. elastase, collagenase, & cathepsin)

Their action is checked by: Serum antiproteases (e.g. α1-antitrypsin)

Neuropeptides • Small proteins • Secreted by nerve fibers mainly in lung & GIT • Initiate inflammatory response • Substance P :  Transmits pain signals  Regulates vessel tone  Modulates vascular permeability

Chemical Mediators of Inflammation

Cell-Derived

Plasma-Protein-Derived Vasoactive Amines

Eicosanoids PAF Cytokines Chemokines ROS NO Lysosomal Enzymes of Leukocytes Neuropeptides

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