1.
Mediators of inflammation
2
Definition: Chemical mediators that are
responsible for vascular and
cellular events.
• It may either of two types,
– Cell Derived - produced locally by
cells at the site of inflammation
– Plasma derived – mainly from liver
• Some mediators are derived from
Necrotic cells

2.
Classification
3
Cell derived mediators
Plasma derived mediators

3.
4

4.
1. Cell derived mediators
5
a) vasoactive amines(serotonin,histamine)
b) Arachidonic acid metabolites
 cycloxygenase pathway
 lipoxygenase pathway
c) Lysosomal components
d) Platelet activating factor
e)Cytokines (IL-1,TNF-α,TNF-β,IF-γ,Chemokines)
f) Nitric oxide andoxygen metabolites

5.
a) Vasoactive amines
Histamine :- Histamine is an organic nitrogenous compound as well
as regulating physiological function in the gut and acting as a
neurotransmitter for the brain, spinal cord, and uterus.
Mast cells are richest source of histamine,
basophiles and platelets.
Released by the stimuli of various agents like Heat, Cold,
Irradiation, Irritant chemicals,Anaphilatoxins,
Interleukins,.. etc.
Actions ; Vasodilation
Vascularpermeability
Itching and pain
6

6.
Serotonin/5-hydroxy tryptamine :-
The scientific name for serotonin is 5-hydroxytryptamine,
or 5-HT. It is mainly found in the chromafin cells of GIT,
Spleen,Nervous tissue, Mast cells,Platelets. brain,
bowels, and blood.
Actions ;
Similar to Histamine, but lesspotent
Vasodilation
Vascularpermeability
7

7.
b) Arachidonic acid Metabolites
Arachidonic acid is a polyunsaturated fatty acid
• produced by endothelial cells, leukocytes and platelets
• act locally on smooth muscle, endothelium and platelets
• origin:
Arachidonic acid derived from dietary sources or by conversion
from the linoleic acid.
And released by activated phospholipases (in injury)
• two important pathways:
 cyclooxygenase (COX)
 lipoxygenase

8.
• AA Metabolites
– Cyclooxygenase pathway
• PGD2,PGE2,PGF2α (prostaglandin)
– V.D
– Potentiates Edema formation
• PGI2(prostacyclin)
– Produced by prostacyclin synthase in endothelial cell
– V.D, Inhibits Platelet aggregation
• TxA2( throboxane A2)
– Produced by Thromboxane synthase in pllatelets
– stimulates platelets aggregation

9.
Cyclooxygenase Pathway

10.
– Lipoxygenase Pathway: present in neutrophils
• 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
• PAF Platelet-activating factor, or AGEPC (acetyl-glyceryl-ether-
phosphorylcholine), is a potent phospholipid activator and mediator of many
leukocyte functions,platelet aggregation
• Produced by WBCs & endothelial cells
• Causes V.C, Bronchoconstriction

11.
Lipoxygenase Pathway
HPETE,
hydroperoxyeicosatetraenoic
acid.
HETE,
hydroxyeicosatetraenoic acid;

12.
Major effects of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in
inflammation

13.
c) Lysosomal components
1
4
Source :- Neutrophiles andmonocytes
Potent mediators
Realease of acid proteases, collagenase,elastase,
plasminogen activator
Lysosomes contain a wide variety of enzymes such as nucleic
acids, proteins, and polysaccharides.

14.
d) Platelet activating factor
 Phospholipid derived mediator
 Released from :- Platelets, basophil, mastcells,
neutrophils macrophages, endothelialcells
 Actions :-
 Vascularpermeability
 Vasoconstriction
 Vasodilatation
15
Also known as PAF, or AGEPC (acetyl-glyceryl-ether-
phosphorylcholine), is a potent phospholipid activator
and mediator of many leukocyte functions, platelet aggregation
and degranulation, inflammation,

15.
e) Cytokines
16
“Cytokines are proteins produced by many cell
types (activated lymphocytes, macrophages,
and dendritic cells).”
• Cytokines
– Some mediate communication between
WBCs(Interleukins)
– Some play role in inflammation(TNF, IL-1,
Chemokines, IFN-γ ,IL-12)
– mediate and regulate immune and
inflammatory reactions

16.
Actions :-
 Adhesion of leucocytes toendothelium
 S ynthesis of Prostacyclin, which is avasodilatorand
anti aggregator of platelets
 Synthesis of thrombogenic effecton
endothelial surface
17

17.
f) Nitric oxide and oxygen metabolites
18
Functions of nitric oxide (NO) in blood vessels and macrophages, produced by two NO
synthase enzymes. NO causes vasodilation, and NO free radicals are toxic to microbial and
mammalian cells. NOS: nitric oxide synthase.

18.
2.Plasma derived mediators
19
a) The kininsystem :
b) The clottingsystem :
c) The fibrinolyticsystem :
d) The complementsystem :

19.
2: Plasma Protein derived mediators
Pa
a)Kinin System: The kinin– kallikrein system or
simply kinin system is a poorly hormonal system .
It consists of blood proteins that play a role in
inflammation, blood pressure control, coagulation and
pain.
– Ultimately leads to formation of bradykinin
– Bradykinin causes
– Arteriolar dilation, increases vascular permeability &
broncho constriction

20.
a) The kinin system
factorXII
contact
factorXIIa
prekallikrein activator
Plasmaprekallikrein kallikrein
kininogen Bradykinin
blood vessels to
dilate (enlarge)
21

21.
• Clotting System: Coagulation, also known
as clotting, is the process by which blood
changes from a liquid to a gel, forming a
blood clot
– 12a → 11a → 10a → 2a (Thrombin)
– Thrombin converts fibrinogen into fibrin &
generates fibrinopeptides
– Fibrinopeptides → Increased Vascular
permeability & chemotactic for WBCs

22.
b) Clotting system
factorXII
contact
factorXIIa
XI XIa +VIIa +PF3
X Xa +Va+PF3
prothrombin thrombin
fibrino fibrinogen fibrin
Peptides plasmin
23

23.
Fibrinolytic System: to remove the clot after the
vasculature is repaired, as well as to degrade
clots that form in the bloodstream.
– 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

24.
C) Fibrinolytic system
25

25.
– Mainly leads to the formation of C3a & C5a
– Vascular effects( C3a & C5a)
– Leukocyte activation, adhesion,
chemotaxis(C5a)
– Phagocytosis(C3b,iC3b)
Complement System: The complement system is a
collection of soluble proteins
The complement system is a part of the immune system
that enhances (complements) the ability of antibodies and
phagocytic cells to microbes and damaged cells from an
organism,
promotes inflammation, and attacks the pathogen's plasma
membrane
 Membraneattackcomplexcausepores in cell of invading microbes.

26.
Three pathways:
• Classical pathway (antibodies)
• Alternate pathway (microbe LPS)
• Lectin pathway (sugar on microbes)

27.
Interrelationships between the four plasma mediator systems triggered by
activation of factor XII (Hageman factor). Note that thrombin induces inflammation
by binding to protease-activated receptors (principally PAR-1) on platelets,
endothelium, smooth muscle cells, and other cells.