mediators of inflammation

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INFLAMMATORY MEDIATORS

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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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CLASSIFICATION Exogenous / Endogenous

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Cell derived & Plasma derived

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CELL DERIVED INFLAMMATORY

MEDIATORS

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VASOACTIVE AMINES

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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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Antiproteases in serum & tissue fluids α1- antitrypsin

α2- macroglobin

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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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PROSTAGLANDIN

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LEUKOTRIENES

Lipoxins

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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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`

Lipooxygenase inhibitorTriclosan

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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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TUMOR NECROSIS FACTOR & INTERLEUKIN 1

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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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CYTOKINE & PERIODONTAL TISSUE

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CYTOKINE & ALVEOLAR BONE LOSS

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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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INFLAMMATORY MEDIATORS

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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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Inactive form

Most abundant component C3

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C3 Convertase

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C5 Convertase C5b

C5a

C6-C9

MAC

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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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Gingival crevicular fluid:

In healthy individuals 3%

In periodontal inflammation: increased

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COAGULATION SYSTEM

Inflammatio

n

Blood clottin

g

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thrombin

fibrin

Blood clotting

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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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KININ SYSTEM Vasoactive peptides kininogen

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Vascular permeabilitySm0oth muscleBlood vesselsPain

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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

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