mediators of inflammation
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Transcript of mediators of inflammation
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CONTENTS Introduction Properties & General principles Classification Cell derived inflammatory mediators Plasma derived inflammatory mediators Conclusion References
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INTRODUCTION
Permeability factors
Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response.
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PROPERTIES & GENERAL PRINCIPLES
Mediators are generated either from cells or from plasma proteins
Active mediators are produced in response to various stimuli
One mediator can stimulate the release of other mediators
Mediators vary in their range of cellular targets
Once activated & released from the cell, most of these are short lived
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HISTAMINE Mast cells, basophils & platelets
Enzyme Histidine decarboxylase (HDC)
Histamine receptors:- G-Protein coupled receptor superfamily.
H1R, H2R, H3R, H4R H1 receptors
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Direct Indire
ct
Release of histamine
Phosphorylation of IAP
Increased vascular
permeability
Release of histamine
Release of cytokines &
inflammatory mediators
Increase inflammatory
response
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Increase in salivary histamine levels is correlated with the severity of periodontitis (Venza et al 2006)
Gingival fibroblasts mainly express H1R. H2R mRNA also expressed but not much
significant (T
Minami et al)
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SEROTONIN 5- Hydroxytryptamine Chromaffin cells of GIT, spleen, nervous
tissue, mast cells, platelets Action similar to histamine
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LYSOSOMAL ENZYMES Granules of neutrophils:• Specific / secondary • Azurophil / primary
Granules of monocytes & macrophages
Acid proteasesNeutral proteases
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ARACHIDONIC ACID METABOLITES
Eicosanoids 20 carbon polyunsaturated fatty acid,
eicosatetraenoic acid Sources: diet, essential fatty acid- linoleic
acid
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PROSTAGLANDINS IN PERIODONTAL DISEASE
Both gingival and periodontal ligament fibroblasts secrete prostaglandin E in response to IL-1-β
PGE2 in periodontal sites demonstrating inflammation & attachment loss (Offenbacher 1999)
Induction of Osteoclastic bone resorption
PGE2 is released from monocytes of patients with aggressive periodontitis (Offenbacher )
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PGI – antiproliferative effect Cyclosporin A has dose dependent inhibitory
effect on PGI synthesis in gingival tissues.
Nell A et al 1996
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PLATELET ACTIVATING FACTOR
Phospholipid derived mediator
Platelets, basophil, mast cells, neutrophils macrophages, endothelial cells
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vascular permeability Vasoconstriction Vasodilatation Bronchoconstriction Adhesion of leukocytes to endothelium Chemotaxis, degranulation
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ACTIVATED OXYGEN SPECIES
Leukocytes NADPH oxidase system Chemokines, cytokines, endothelial adhesion
molecules
Responses in inflammation: Endothelial cell damage Injury to other cell types Inactivation of antiproteases
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Antioxidants: Enzyme Superoxide dismutase Enzyme catalase Glutathione peroxidase Serum Ceruloplasmin Serum Transferrin
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NITRIC OXIDE Endothelium derived relaxing factor Macrophages, endothelial cells, neurons Paracrine L-Arginine by enzyme nitric oxide synthetase
(NOS)
Endothelial (eNOS) Neuronal (nNOS) Inducible (iNOS)
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CYTOKINES
Cytokines are a diverse group of small protein molecules with potent biological activity whose main function is in the regulation of immune responses.
Lymphokines
Autocrine Paracrine Docrine
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Interleukins Interferons Tumor necrosis factor Chemokines Transforming growth factor-beta Adipokines- leptin & adiponectin
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CLASSIFICATION OF CYTOKINES
Proinflammatory cytokines: IL- 1, IL- 6 & TNF
Chemotactic cytokines: IL- 8
Lymphocytes signalling cytokines: cytokines released by Th1: IL-2, IFN cytokines released by Th2: IL- 4, IL- 5, IL-
10, IL-13
Jan Lindhe
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Characteristic of cytokines: Cytokines that regulate lymphocytes: IL-2, IL-4 Cytokines that activate inflammatory cells: Interferon γ, TNF β Cytokines that stimulate haematopoiesis: IL- 3, IL- 7 Colony stimulating factors: Gm- CSF
Slots
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CHEMOKINES Chemokines are a family of small (8-10 kD)
proteins that act primarily as chemoattractants for specific type of leukocytes
4 major group: C-X-C chemokines (α chemokines) C-C chemokines (β chemokines) C chemokines (γ chemokines) CX3C chemokines
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7 transmembrane G protein-coupled receptor
Two main functions: Stimulate leukocyte recruitment in
inflammation
Control of normal migration of cells through various tissues
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INHIBITORS OF DESTRUCTIVE CYTOKINES
Anti-inflammatory cytokines: IL- 1 receptor antagonist (IL-1ra) Transforming growth factor β Interferon γ
Angiogenesis: IL-1β , TNF-α
Fibrogenic cytokines: IL-1β, IL-1α
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Anti-inflammatory activities on bone: Blocking cytokine induced activation: IFN-γ -----> IL-1 & TNF α - induced
osteoclast activation
IL-1ra -----> IL-1 ( α & β ), TNF α
Blocking osteoclast formation: TGF- β
Activation of osteoblasts: FGF, PDGF & Insulin like growth factors I
& II
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CONTENTS Introduction Properties & General principles Classification Cell derived inflammatory mediators Plasma derived inflammatory mediators Conclusion References
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COMPLEMENT SYSTEM
30 proteins, C1 through C9 Innate & Adaptive immunity Increased vascular permeability, chemotaxis
& opsonization
Complement refers to a system of factors which occur in normal serum and activated characteristically by antigen-antibody interaction & subsequently mediate a number of biologically significant consequences
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Central component of inflammation
Vasoactive substance kinin-like C2a
Molecules anaphylatoxins C3a, C5a
Chemotaxin C5a
Opsonin C3b
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Cell associated & circulatory regulated proteins
Inhibit production of active complement fragments
Normal cells
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Activate mediator system
Inflammation
Coagulation factorsPro-thrombogenicAnticogulant mechanism
CLOTTING
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Chemokines Cytokines Endothelial adhesion molecules Prostaglandins PAF & NO
Protease-activated Receptor (PAR)
Inflammation
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Bradykinin, C3a & C5a - mediators of increased vascular permeability
C5a – mediator of chemotaxis
Thrombin – effect on endothelial cell types
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C3a & C5a generated by several types of reaction:
Immunological reactions
Activation of alternate & lectin pathway by microbes
Agents not directly related to immune responses
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Activated Hegman factor initiates 4 factors involved in inflammatory response:
Kinin system
Clotting system
Fibrinolytic system
Compliment system
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REFERENCES Pathologic Basics of diseases, Robbins &
Cotran, 8th edition Clinical periodontology, Carranza, 10th
edition Clinical periodontology, Carranza, 8th edition Clinical periodontology & implant dentistry,
Lindhe, 5th edition Periodontics, Grant, 6th edition Ericag Emmellr,o Dericki . Marshal&l G
Regorjy. Seymour, Cytokines and prostaglandins in immune homeostasis and tissue destruction in periodontal disease, PeriodontoIogy 2000. Vol. 14. 1997, 112-143