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!