1. Chemical
Mediators of
Inflamation
By: Ahsan Shafiq
Page 1

2. Origin
• Locally by cells(cell derived
mediators)
• Liver
– Inactive precursors in
plasma(plasma protein derived
mediators)
Page 2

3. Cell derived Mediators
• Preformed in secretory
granules→Vasoactive Amines e.g
Histamine, serotonin
• Newly Synthesized
a. Arachidonic Acid
Metabolites(PGS, PGI2, TXA2, LTS, LXS)
b. TNF, IL-1
c. Cytokines
d. ROS
e. NO
f. Neuropeptides
g. PAF
h. Lysosomal Enzymes of WBCs
Page 3

4. Plasma Protein Derived mediators
• Complement System
• Coagulation & Kinin System
Page 4

5. Cell Derived Mediators
• Histamine
• Produced by circulating basophils,
platelets & massed cells adjacent to
vessels
• Produced in response to physical
injury,immune
reactions, neuropeptides, C3a &
C5a, Cytokines, WBC-derived
Histamine releasing protein
• Vasodilatation, Increase vascular
permeability, Endothelial activation
Page 5

6. Cell Derived Mediators
• Serotonin
• Produced mainly within platelets dense
body granules
• Released during platelet aggregation
• Cause vasodilatation, Increase vascular
permeability
Page 6

7. Cell Derived Mediators
• AA Metabolites
– Cyclooxygenase pathway
• PGD2,PGE2,PGF2α
– V.D
– Potentiates Edema formation
• PGI2
– Produced by prostacyclin synthase in endothelial
cell
– V.D, Inhibits Platelet aggregation
• TxA2
– Produced by Thromboxane synthase in pllatelets
– V.C & stimulates platelets aggregation
Page 7

8. Cell Derived Mediators
– Lipoxygenase Pathway
• LTB4
– Produced by neutrophils & some macrophages
– Chemotactic agent for neutrophils
• LTC4,LTD4 & LTE4
– Produced by mast cells
– V.C bronchospasm
• Lipoxins
– Endogenous antagonists of Leukotrienes
Page 8

9. Cell Derived Mediators
• PAF
• Produced by WBCs & endothelial
cells
• Causes V.C, Bronchoconstriction
Page 9

10. Cell Derived Mediators
• Cytokines
– Some stimulate bone marrow
precursors to produce more WBCs
– Some mediate communication
between WBCs(Interleukins)
– Some play role in inflammation(TNF,
IL-1, Chemokines, IFN-γ ,IL-12)
Page 10

11. Cell Derived Mediators
• TNF & IL-1
– Endothelial effects
• Endothelial activation
• WBC binding & recruitment
• Procoagulant activity
• Increase in IL-1,IL-6,IL-8,PDGF
eicosanoids
– Fibroblast effects
• Activates tissue fibroblasts
• Increases proliferation
• Production of collagen &ECM Page 11

12. Cell Derived Mediators
– Systemic Effects
• Fever
• Lethargy
• Increased sleep
• Decreased appetite
• Hepatic synthesis of acute phase proteins
• Metabolic wasting
• Corticosteroids Synthesis
Page 12

13. Cell Derived Mediators
• Chemokines
– Helps in recruitment of Leukocytes
– Responsible for anatomic distribution of
B & T lymphocytes in different areas of
lymph nodes & spleen
Page 13

14. Cell Derived Mediators
• ROS
– Produced by NADPH oxidase in
neutrophils & macrphages
– At low levels, increases cytokines &
adhesion molecule expression ,destroy
phagocytosed microbes & necrotic tissues
– At high levels, cause tissue injury by
endothelial damage, breakdown of ECM &
direct injury to other cell types
– Protective mechanisms(
Catalase, Superoxide dismutase &
Glutathione)
Page 14

15. Cell Derived Mediators
• NO
– Produced by neurons, macrophages &
endothelial cells
– nNOS, iNOS (IL-1, TNF, IFN-γ,
bacterial endotoxins),eNOS
– Functions
• V.D
• Inhibits platelet adhesion,aggregation &
degranulation
• Inhibits WBC adhesion & recruitment
• Cytotoxic to microbes(Microbicidal)
Page 15

16. Cell Derived Mediators
• Lysosomal Enzymes of WBCs
– Acid proteases
• Active only within phagolysosomes
– Neutral proteases
• Elastase,Collagenase,Cathepsin
• Active in ECM
• Degrade elastin, collagen & other matrix
proteins
• Convert C3 & C5 to C3A & C5A
• Can convert HMWK to Bradykinin
Page 16

17. Cell Derived Mediators
• Neuropeptides ( e.g Substance P)
– Transmit pain signals
– Regulate vessel tone & thus vascular
permeability
Page 17

18. Plasma Protein derived mediators
• Complement System
– Consists of Plasma proteins
– Upon activation different complement
proteins(C3b) coat/opsonize microbes for
phagocytosis & destruction
– C3a & C5a cause mass cells to release
histamine which inturn causes V.D thus
increasing vascular permeability
– C5a activates lipoxygenase pathway
causing release of more inflammatory
mediators
– C5a also helps in leukocyte
activation, adhesion & chemotaxis
Page 18

19. Plasma Protein derived mediators
• Coagulation & Kinin System
– Hageman factor/Factor12a
• A protein synthesized by liver
• Circulates in an inactive form in plasma
• Activated by collagen basement
membrane or activated platelets
• Activated with the help of HMWK &
kallikrein
• Activated factor12 further activates
– Kinin System
– Clotting System
– Fibrinolytic System
– Complement System
Page 19

20. Plasma Protein derived mediators
• Kinin System
– Ultimately leads to formation of
bradykinin
– Bradykinin causes arteriolar
dilation, increases vascular permeability
& broncho constriction
• Clotting System
– 12a → 11a → 10a → 2a (Thrombin)
– Thrombin converts fibrinogen into fibrin
& generates fibrinopeptides
– Fibrinopeptides → Increased Vascular
permeability & chemotactic for WBCs
Page 20

21. Plasma Protein derived mediators
• Fibrinolytic System
– Ultimately leads to formation of
plasmin
– Plasmin
• converts C3 to C3a
• Converts factor-12 to factor-12a
• Breaks down fibrin to fibrin degradation
products which further increases the
vascular permeability
Page 21

22. Plasma Protein derived mediators
• Complement System
– Mainly leads to the formation of C3a
& C5a
– Vascular effects( C3a & C5a)
– Leukocyte activation, adhesion,
chemotaxis(C5a)
– Phagocytosis(C3b,iC3b)
Page 22