Download Inflammation 3

Inflammation
Dr. Ahmad Hameed
MBBS,DCP, M.Phil
Chemical Mediators and regulators of
inflammation

Chemical mediators that are responsible for
vascular and cellular events of inflammation.

Mediators may be produced locally by cells at
inflammation, or may be derived from circulating
precursors (typically synthesized by the liver) that
are released at the site of inflammation.
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Cell-derived mediators are



.
Sequestered intracellular granules or synthesized de novo
Plasma derived mediators are inactive which undergo
proteolytic cleavage to acquire biologic activity.
Chemical Mediators and regulators of
inflammation

Most mediators act by binding
receptors on different target cells.






specific
Diverse action
Direct action
The actions of most mediators
regulated and short lived

to
Quickly decay
Inactivated by enzymes
Eliminated
inhibited
are
tightly
Cell Derived
Mediators
Source
Actions
Preformed mediators in
secretory granules
Histamine
Mast cells, basophils,
platelets
Vasolidation, increased vascular
permeability, endothelial activation
Serotonin
Platelets
Vasoconstriction
Prostaglandins
All leukocytes, mast cells
Vasodilation, pain, fever
Leukotrienes
All leukocytes, mast cells
Increase vascular permeability,
chemotaxis, leukocyte adhesion and
activation
Plateletactivitating
factor
All leukocytes, EC
Vasodilation, increase vascular
permeability, leukocyte adhesion,
chemotaxis, degranulation, oxidative
burst.
Reactive
oxygen species
All leukocytes
Killing microbes, tissue damage
Nitric oxide
Macrophages, EC
Vascular smooth muscle relaxation;
killing of microbes
Cytokines
Macrophages,lymphocytes,
EC, mast cells
Local; endothelial activation
(expression of adhesion molecules)
systemic: fever, metabolic
abnormalities, hypotension (shock)
Neuropeptides
Leukocytes, nerve fibers
Newly synthesized
Plasma proteinderived
Mediators
Source
Actions
Compliment activation
C3a
(anaphylatoxins
)
Plasma
(Liver)
Leukocyte chemotaxis and activation, direct target
killing (MAC), yasodilation (mast,cell stimulation)
C5a
(anaphylatoxins
)
Plasma
(Liver)
C3b
Plasma
(Liver)
C5b-9
(membrance
attack complex)
Plasma
(Liver)
Kinin system
(bradykinin)
Plasma
(Liver)
Coagulation /
fibrinolysis
sytem
Plasma
(Liver)
Factor XII (hageman
factor) activation
Increased vascular permeability, smooth muscle
contraction, vasodilation, pain
Cell-Derived Mediators
Tissue macrophages, mast cells, and endothelial cells,
leukocytes
Vasoactive Amines
HISTAMINE
Richest source
 Mast cells ( C.T , B.V)
 Basophils
 Platelets
Release in response to
1.
Physical injury (trauma, cold, heat)
2.
Immune reactions (Antibody to mast cells)
3.
Anaphylatoxins (C3a & C5a)

Histamine Releasing protein (H.R.P) from leucocytes
2.
Neuropeptides (Substance P )
3.
Cytokines ( IL-1, IL-8)
Action
 Immediate transient response (main)
 Dilatation of arterioles
 Increase permeability of venules
 Contricts large arteries
 Acts on microcirculation / bind to H1 receptors on endothelial
cells
1.
SEROTONIN
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5HT
Similar action
Present in platelets, entero chromaffin cells & neurons
Neurotrasmitter and regulate intestinal motility
When platelet aggregation occurs  release serotonin
Mast cells PAF  platelet aggregation
Archidonic Acid Metabolites:
Prostaglandins, Leukotrienes and Lipoxins
Microbial Products + Mediators of Inflammation
↓
Arachidonic Acid
Prostaglandins
Leukotrienes
AA Metabolites

Cyclooxygenase pathway
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PGs are Produced by mast cells, macrophages,
endothelium and others
PGE2,PGD2,PGF2α
 Vasodilation
 Potentiates Edema formation
 Involved in pathogenesis of pain and fever
PGI2
 Produced by prostacyclin synthase in endothelial
cell
 Vasodilation, Inhibits Platelet aggregation
TXA2
 Produced by Thromboxane synthase in platelets
 Vasoconstriction & stimulates platelets
aggregation, unstable and converts to TXB2
Production of arachidonic acid metabolites and their
roles in inflammation.
Lipoxygenase Pathway
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LTs are secreted mainly by leukocytes and
chemoattractants for leukocytes.
LTA4
LTB4
 Produced by neutrophils & some macrophages
 Chemotactic agent for neutrophils
LTC4
LTD4 & LTE4
 Produced by mast cells
 Vasocontriction + bronchospasm + Intravascular
Permeability
Anti-inflammatory Drugs that
Block Prostagladin Production
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NSAID
 Inhibit cyclooxygenase
 Prevent biosynthesis of all PG
 Treat pain and fever
Cyclooxygenase inhibitor
 Two isoforms - COX-1/COX-2
 COX-1
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Expressed on most tissues produced in response to
inflammation stimulate prostaglandins
COX-2
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Absent most tissues
Developed that they will not affect protective function of
prostaglandins
Increased risk of cerebrovascular and cardiovascular
events
Lipoxygenase Pathway
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Lipoxins (Anti inflammatory mediators )
 Endogenous antagonists of Leukotrienes ie inhibit
neutrophil chemotaxis and adhesion to
endothelium
 Platelet adherent to neutrophils from LXA4 and
LXB4

Cortisol

Reduces vascular permeability and edema

Decreases prostglandin production by
preventing release of AA by inhibiting
phospholipase A2
Platelet-Activating Factor
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It is generated from a lipid complex stored in
cell membranes; Produced by WBCs &
endothelial cells
induces platelet aggregation;
Causes Vasoconstriction, Bronchoconstriction
It activates neutrophils and is a potent
eosinophil chemoattractant;
It contributes to extravascularization of plasma
proteins and so, to edema.