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Transcript
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
THANKS!
Have a nice day &
a GREAT weekend!