chemical mediators of inflammation

1. Aiswarya Thomas
APSC Pariyaram

2. CHEMICAL MEDIATORS OF INFLAMMATION
 Also called as permeability factors or endogenous
mediators of increased vascular permeability
 Large and increasing number of endogenous
compounds which can enhance vascular permeability
 Chemical mediators are released from cells, plasma,
or damaged tissue

3. 1. CELL DERIVED MEDIATORS
 Vasoactive amines (Histamine, 5-hydroxy
tryptamine, neuropeptides)
 Arachidonic acid metabolites (Eicosanoids)
 Metabolites via cyclo-oxygenase pathway
(prostaglandins, thromboxane
A2,prostacyclin,resolvins)
 Metabolites via lipo-oxygenase pathway (5-
HETE,leukotrienes,lipoxins)
 Lysosomal components (from PMNs ,macrophages)
 Platelet activating factor
 Cytokines(IL-1,TNF-α,TNF-β,Chemokines )
 Free radicals (oxygen metabolites ,nitric oxide)

4. 2. PLASMA DERIVED MEDIATORS
Products of
The kinin system
The clotting system
The fibinolytic system
The complement system

5. 1. CELL DERIVED MEDIATORS
1. VASOACTIVE AMINES
¡) Histamine
 Stored in the granules of mast cells, basophils and
platelets.
Main actions
Vasodialation, incresed vascular permeability, itching,
pain
¡¡) 5-Hydroxytryptamine
 Present in tissues like chromaffin cells of GIT,
spleen, nervous tissue, mast cells and platelets.

6. ¡¡¡)Neuropeptides
Produced in the central and peripheral nervous
systems.
Main actions
¡) Increased vascular permeability
¡¡) Trasmission of pain stimuli
¡¡¡) Mast cell degranulation

7. 2. ARACHIDONIC ACID METABOLITES
(EICOSANOIDS)
• Arachidonic acid (fatty acid) is released from the
cell membrane by phospholipases.
• It is then activated to form arachidonic acid
metabolites or eicosanoids by one of the
following two pathways: cyclo - oxygenase and
lipo – oxygenase pathway

8. Metabolites via cyclo oxygenase pathway
Activated arachidonic acid
Cyclo-oxygenase
PGG2 PGH2 + Free oxygen radical
PGD2,PGE2
Vasodilator
Bronchodilator
↑ permeability
PGF2-α
Vasodilator
bronchoconsticto
r
TXA2
Vasoconstictor
Bronchoconstrict
or
Platelet
aggregation
PGI2
Vasodilator
Bronchodilator
Anti-
aggregating
agent
RESOLVINS
Inhibitor of
pro-
inflammatory
cytokines

9. • Metabolites via lipo oxygenase pathway
Activated arachidonic acid
Lipo -oxygenase
5-HPETE 5-HETE
LTA4
LTB4
Chemotactic
Cell
adherence
LTC4 LTD4 LTE4
LIPOXINS
Smooth muscle constrictor
Vasoconstrictor
Bronchoconstrictor
↑Vascular permeability

10. 3. LYSOSOMAL COMPONENTS
 The inflammatory cells neutrophils and
monocytes contain lysosomal granules which on
release elaborate a variety of mediators.
¡) Granules of monocytes and tissue macrophages
 On degranulation these cells release acid
proteases, collagenase , elastase and
plasminogen activator

11. ¡¡)Granules of neutrophils
PRIMARY SECONDAR
Y
TERTIARY
Contain
myeloperoxidase,
acid hydrolases,
acid phosphatase,
phospholipase,
elastase and
protease.
Contain
Alkaline
phosphatase,
gelatinase,
collagenase,
lysozyme, vitamin
b12, binding
proteins
Contain
Gelatinase
and acid
hydrolase.

12. 4. PLATELET ACTIVATING FACTOR (PAF)
 Released from IgE sensitised basophils or mast
cells, leucocytes, endothelium and platelets.
ACTIONS
 Increased vascular permeability
 Vasodialation and vasoconstiction
 Bronchoconstriction
 Adhesion of leucocytes to endothelium
 Chemotaxis

13. 5. CYTOKINES
 These are polypeptide substances produced by
activated lymphocytes (lymphokines) and
activated monocytes (monokines)
 Major cytokines- interleukin-1(IL-1), tumour
necrosis factor (TNF)α and β, Chemokines.
ACTIONS
IL-1 and TNF-α, TNF-β
Induce endothelial effects-
• Increased leucocyte adherece
• Thrombogenicity
• Fibroblastic proliferation

14. IFN-Y
• Activation of macrophages and neutrophils
• Synthesis of nitric acid synthase
Chemokines
• IL-8 Chemotactic for neutrophils
• Eotaxin chemotactic for eosinophil

15. 6. FREE RADICALS:OXYGEN METABOLITES
AND NITRIC OXIDE.
¡)Oxygen derived metabolites
 Released from activated neutrophils and
macrophages.
ACTIONS
• Endothelial cell damage and there by increased
vascular permeability
• Activation of protease and inactivation of
antiprotease causing tissue matrix damage

16. ¡¡)Nitric oxide (NO)
 Formed by activated macrophages
ACTIONS
• Vasodialation
• Anti-platelet activating agent

17. 2. PLASMA DERIVED MEDIATORS
These include the various products derived from
activation and interaction of 4 interlinked
systems: kinin, clotting, fibinolytic and
complement.
oHageman factor(factor xii) of clotting system
plays a key role in interactions of the 4 systems.
oActivation of factor xii in vivo by contact with
basement membrane and bacterial endotoxins,
and in vitro with glass or kaolin leads to
activation of clotting, fibrinolytic, and kinin
systems.
oThe end products of the activated clotting,
fibrinolytic and kinin system activate the

18. Factor XII
contact
Factor XII a
FIBRINOLYTIC SYSTEM CLOTTING SYSTEM KININ
SYSTEM
Plasminogen Prothrombin Plasma
prekallikrein
prekallikrein
Plasminogen activator
activator Thrombin Kallikrein
Plasmin Fibrin Kininogen
Fibrin split products Bradykinin
COMPLEMENT SYSTEM
Permeability factors (C3a, C5a), MAC (C5b,C9)

19. BRADYKININ
ACTIONS
Smooth muscle contraction
Vasodilation
Increased vascular permeability
Pain
FIBRINOPEPTIDES
Increased vascular permeability
Chemotaxis
Anticoagulant activity

20. THE COMPLEMENT SYSTEM
I. The activation of complement systemcan occur
by:
i. Classic pathway via non immunological agents
ii. Alternate pathway via non immunological
agents
 Complement system on activation yields
activated products – anaphylotoxins (C3a, C4a,
C5a) and membrane attack complex (MAC) –
C5b, C6, C7….
ACTIONS
 C3a, C5a,C4a activate mast cells and basophils
 C3b is an opsonin
 C5a is chemotactic for leucocytes