Download chemical mediators of inflammation

CHEMICAL MEDIATORS
OF INFLAMMATION
DR SUBHAN ALI R., M.D
ASSISTANT PROFESSOR
PATHOLOGY
DEFINITION
Short
acting
chemical
substances which are derived
from cells or plasma that
mediate
various
events
in
inflammation.
GENERAL PRINCIPLES
Origin:
Plasma or present in cells.
Plasma derived mediators: Precursor form
and need to be activated.
Cell derived mediators: Present within
granules.
Cells:
Neutrophils,
macrophages,
monocytes, platelets.
GENERAL PRINCIPLES
Triggering factor:
Microbial products.
Host proteins – complement, kinin and
coagulation system.
Damaged tissue.
GENERAL PRINCIPLES
Mechanism of action:
Short half-life.
Bind to specific receptors on target cells.
Act by enzymatic action or mediate
oxidative damage.
Stimulate cells to release chemical
mediators.
Act on single or many target cells.
CLASSIFICATION
• Cell derived.
• Plasma proteins.
CELL DERIVED:
1. Vasoactive amines: Histamine and
serotonin.
2. Arachidonic acid metabolites: PG, LT,
lipoxins.
3. Platelet activating factor.
4. Reactive oxygen species.
5. Nitric oxide.
6. Cytokines and chemokines.
7. Lysosomal constituents of leucocytes
8. Neuropeptides.
PLASMA DERIVED – PROTEINS
• Complement system
• Clotting system
• Kinin system
CELL DERIVED:
• Derived from the cells.
• WBCS, mast cells, platelets, endothelium,
macrophages.
1. VASOACTIVE AMINES
• Preformed mediators.
• First
mediators
to
be
inflammation.
• Histamine and serotonin.
released
during
A. HISTAMINE
• Mast cells; richest source; basophils and
platelets.
• Preformed and stored in granules;
released during inflammatory stimulus.
• Stimuli: Physical injury (cold, heat) allergy,
neuropeptides, CK (IL-1, IL-8).
• Vasodilation,
increased
vascular
permiability.
B. SEROTONIN
• 5 – hydroxytryptamine.
• Platelets and enterchromaffin cells.
• Preformed.
• Release from platelets is stimulated by
platelet aggregation.
• Action similar to histamine.
2. ARACHIDONIC ACID
METABOLITES
• Arachidonic acid, polyunsaturated fatty
acid, esterified form in cell membrane
phospholipid.
• Physical, chemical or mechanical stimuli
 activates phospholipase A2  releases
arachidonic
acid
from
membrane
phospholipid.
• Arachidonic acid metabolites; eicosanoids;
synthesised by two pathways.
• Cyclooxygenase pathway (COX): Mast
cells,
macrophages,
endothelial
cells.
Prostaglandins (PG) and thromboxane
(Tx).
Cell membrane phospholipid
Phospholipase A2
Steroids
Arachidonic acid
NSAID
Lipooxygenase
5-HETE
LTC4, LTD4, LTE4
Cyclooxygenase
PGI2, PGD2, PGE2
PGF2, TxA2
A. CYCLOOXYGENASE
METABOLITES
• PGI2: Prostacyclin: Vasodilation, inhibits
platelet aggregation.
• PGD2, PGE2, PGF2: Vasodilation.
• TxA2:
Vasoconstriction,
aggregation.
platelet
B. LIPOOXYGENASE
METABOLITES
• 5-HETE: Chemotaxis.
• LTC4, LTD4, LTE4: Vasoconstriction,
smooth muscle contraction, increased
vascular permiability.
• Lipoxins: Inhibit leucocyte recruitment,
inhibit neutrophil chemotaxis, resolution
of inflammatory response.
Action
Mediator
Vasodilation
PGI2 (prostacyclin),
PGE1, PGE2, PGD2
TXA2, LTC4, D4, E4
Vasoconstriction
Increased vascular
permeability
LTC4, D4, E4
Chemotaxis,
leukocyte adhesion
LTB4, HETE
3. PLATELET ACTIVATING
FACTOR (PAF)
• Platelets,
basophils,
mast
cells,
neutrophils, macrophages, monocytes and
endothelial cells.
• Platelet
aggregation,
smooth
muscle
contraction, vasoconstriction, leucocyte
adhesion, chemotaxis.
4. REACTIVE OXYGEN
SPECIES
• Oxygen-derived free radicals.
• Released from leukocytes; exposure to
microbes,
chemokines,
immune
complexes, following phagocytosis.
• Superoxide anion (O2-), hydrogen
peroxide (H2O2) and hydroxyl radical (OH).
• Destroy phagocytosed microbes.
• Released
extracellularly
during
inflammation  tissue damage.
5. NITRIC OXIDE (NO)
• Discovered as factor released from
endothelial cells; cause vasodilation by
relaxing vascular smooth muscle cells.
• Endothelium derived relaxing factor
(EDRF).
• Macrophages and brain neurons.
• Relaxes
smooth
muscle
cells

vasodilation.
• Very short half life (in seconds); act on
cells in close proximity where it is
produced.
• Inhibits platelet aggregation and adhesion.
• Reduces inflammatory response.
6. CYTOKINES (CK)
• Short acting chemical substances released
by inflammatory cells causing cell to cell
interaction and modulate functions of
other cells.
GENERAL PROPERTIES
• Single CK can be produced by many cells.
• Single CK can act on many cells.
• Bind to specific surface receptor and act.
• Autocrine, paracrine
mechanisms.
• Chemokines:
WBCs.
and
endocrine
Chemo-attractants
for
CYTOKINES IN ACUTE
INFLAMMATION
• Tumor necrosis factor (TNF).
• Interleukin – 1 (IL-1).
• Interleukin – 6 (IL-6).
• Chemokines.
TNF AND IL-1
Major types of CK mediate inflammation.
Produced by macrophages.
Stimulus: Endotoxin, microbial products,
immune complexes, physical injury.
Actions:
Effects
on
endothelium,
leukocytes, fibroblasts, induction of
systemic acute-phase reactions (fever,
neutrophilia).
7. LYSOSOMAL
CONSTITUENTS OF
LEUCOCYTES
• Neutrophil and monocyte lysosomal
granules contain hydrolytic enzymes;
bactericidal activity.
• Enzymes released extracellularly during
inflammation  tissue damage.
8. NEUROPEPTIDES
• Substance P and neurokinin A.
• Produced by sensory nerves and WBCs.
• Transmit pain signals, regulate blood
pressure, increase vascular permeability.
PLASMA DERIVED
CHEMICAL MEDIATORS –
PROTEINS
• Complement system
• Clotting system
• Kinin system
1. COMPLEMENT SYSTEM
• Composed of 20 proteins; C1 to C9.
• Increased
vascular
permeability,
chemotaxis, opsonization  defense
against microbial pathogens.
• In plasma; inactive form; C1 to C9.
• Critical step; activation of C3.
• Activation of C3 by three pathways:
classical, alternative and lectin pathways.
• C3  C3a + C3b  C5  C5a + C5b
 C5a+C6 to C9  membrane attack
complex (MAC)  bactericidal.
Action of Complement Derived
Factors
• C3a, C5a: Histamine release, increased
vascular permiability and vasodilation.
• C5a: Chemotactic agent for neutrophils,
monocytes, basophils and eosinophils.
• C3b: Opsonin for phagocytosis by
neutrophils and macrophages.
2. CLOTTING SYSTEM
• Activated by intrinsic and extrinsic
pathways  activation of thrombin.
• Thrombin binds to protease activated
receptors (PAR) present on platelets,
endothelial cells, smooth muscle cells 
production of chemical mediators.
3. KININ SYSTEM
• Bradykinin; vasoactive peptide generated
by plasma protein kininogen by action of
enzymes kallikreins.
• Bradykinin  increased vascular
permiability, smooth muscle contraction,
vasodilation and pain.
SUMMARY
Vasodilation
Increased vascular
permeability
Histamine, PG, NO
Histamine, C3a, C5a, LT,
Kinin, PAF, Substance P
Chemotaxis
C5a, LTB4, chemokines
Leucocyte
movement
IL-1, TNF
Phagocytosis,
Tissue destruction
Lysosomal products,
Oxygen derived radicals