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The Cell-Derived Mediators of Chemical Mediators of
Inflammation
Presented by Sara M. Al-ShakerWed. 5/11/2008
King Saud UniversityRiyadh, 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 productionLocal 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 mediatorsStimulate release of secondary effector
molecules• Actions of most mediators are tightly
regulatedDecay
Enzymatic inactivationEliminationInhibition
Chemical Mediators of Inflammation
Cell-DerivedPlasma-Protein-
Derived
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-DerivedPlasma-Protein-
Derived
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• Stimuli of Release:1. Physical injury2. Immune reactions3. C3a and C5a fragments of complement
(anaphylatoxins)4. Leukocyte-derived histamine-releasing
proteins5. 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:LeukocytesMast cells
Endothelial cellsPlatelets
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 viaphospholipases
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 ofPhospholipase 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 cellsEndothelial cells
• Stimulation:Bacterial endotoxinsImmune 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
inflammation2. 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 viaNADPH oxidase pathway
• Source:Neutrophils and Macrophages
• Stimuli of release:Microbes
Immune complexesCytokines
Nitric Oxide• Short-lived• SOLUBLE• Free-radical gas• Isoforms of NO Synthase (NOS):1. Type I (nNOS) : neuronal, not
significant in inflammation2. Type II (iNOS): inducible, in
macrophages and endothelial cells, NO production in inflammation
3. Type III (eNOS): constitutive, endothelium
NO
• Functions:1. Vasodilation2. Antagonism of platelet activation
(adhesion, aggregation, & degranulation)
3. Reduction of leukocyte recruitment4. 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
THANKS!Have a nice day &a GREAT weekend!