Chemical Mediatorsof Inflammation
Chemical mediators released during inflammation intensify and propagate the inflammatory response.
A chemical mediator is any messenger that acts on blood vessels, inflammatory cells or other cells to
Contribute to an inflammatory response. Thesce mediators are soluble, diffusible molecules that can act
locally and systemically
AISO called as permeability factors or endogenous mediators of increased vascular permeability, these
are a large and increasing number of endogenous compounds identified which can enhance vascular
permeability. However, currently many chemical mediators have been which partake in other
fever, pain and cause tissue
processes of acute inflammation as well e.g, vasodilatation, chemotaxis,
damage. plasma, or
The substances acting as chemicalmediators of inflammation may be released from the cells, the
damaged tissue itself. They are broadly classified into 2 groups:
i) mediators released by cells
i) mediators originating from plasma.
I. CELL-DERIVED MEDIATORS
1. Vasoactive amines (Histamine, 5-hydroxytryptamine, neuropeptides)
2. Arachidonic acid metabolites (Eicosanoids)
i. Metabolites via cyclo-oxygenase pathway (prostaglandins, thromboxane A2, prostacyclin)
ii. Metabolites via lipo-oxygenase pathway (5-HETE, leukotrienes, lipoxins)
3. Lysosomal components (from PMNs, macrophages)
4.Platelet activating factor
5.Cytokines (|L-1, TNF-a, TNF-B, IFN-Y, chemokines)
6. Free radicals (0xygen metabolites, nitricoxide)
II. PLASMA-DERIVED MEDIATORS (PLASMA PROTEASES):Products of:
1. The kinin system
2. The clotting system
3. The fibrinolytic system
4. The complement system
1) Vasoactive Amines
increased
Histamine and serotonin are believed to be the primary mediators in the immediate active phase of
permeability. Vasoactive amines cause vasodilation and increased vascular permeability by causing
endothelial cells to round up, increasing intercellular gaps, and also increasing vesiculovacuolar transfer of
fluids. Vasoactive amines are stored within cells for immediate release.
Histamine
Extensively distributed in tissues, the main source being the mast cells that are normally present in the
perivascular connective tissue; it is preformed and stored in granules with heparin.
Histamine is important mainly in early inflammatory responses and in type 1 hypersensitivity
reactions.
Histamine is important in the immediate active phase of increased vascular permeability.
It is alsoimportant in allergic reactions as it promotes contraction of extravascular smooth muscles in
the bronchi and stimulates stromal cells to synthesize and release eotaxins (chemotaxins for
eosinophils).
The following agents can stimulate release of histamine from mast cells:
Ag (eg pollen) binding to lgE on mast cells
Anaphylotoxins (C3a and CSa)
, Physical injury, mechanical trauma, heat, chemical agents
Snake venoms, toxins, bile salts, ATP
Histaminc-releasing factors from ncutrophils, monocytes, and platelets
Cytokines (|L-I, IL-8)
Neuropeptides, like substance P
Serotonin
It is present in tissues like chromaffincells of GIT, spleen, nervous tissue, mast cells and platelets.
The actions of 5-HT are similar to histamine but it is a less potent mediator of increased vascular
permeability and vasodilatation than histamine.
Neuropeptides.
" Another elass of vasoactive amines is tachykinin neuropeptides, such as substance P, neurokinin A,
vasoactive intestinal polypeptide (VIP) and somatostatin.
" These small peptides are produced in the central and peripheral nervous systems.
The major proinflammatory actions of these neuropeptides is as follows:
a) Increased vascular permeability.
b) Transmission of pain stimuli.
c) Mast cell degranulation.
2)Arachidonic Acid Metabolites
When cells are activated by diverse stimuli, their lipid membranes can be rapidly remodelled to
generate biologically active lipid mediators.
These lipid mediators are like short-range hormones that are formed rapidly and exert their effects
locally and then are inactivated.
Arachidonic acid is a 20-carbon polyunsaturated fatty acid that is derived directly from the diet or by
conversion from linoleic acid.
Arachidonic acid is not free in the cell but esterified in membrane phospholipids; in order to be
released from phospholipids it must be activated by cellular phospholipases, particularly phospholipase
A2 (via mechanical, chemicaland physical stimuli or by other mediators).
Following activation, biosynthesis of the metabolites of arachidonic acid occurs by one of two major
pathways: the cyclooxygenase pathway and the lipoxygenase pathway.
Cyclooxygenase Pathway
Twoenzymes are able to produce these products: COX-1 and COX-2.
COX-1 is normally present (constitutively expressed) and necessary for everyday activities; also
synthesized at sites of inflammation.
COX-2 is transcriptionally regulated - present in various circumstances (eg inflammation).
The main 3 products resulting from this pathway are:
Thromboxane A2 is found in platelets and other cells is a potent platelet aggregator and vasoconstrictor
Prostacyclin (PG I2) is found predominantly in endothelial cells; a potent inhibitor of platelet aggregation
and vasodilator.
Prostaglandins (PG'sE2, D2, F2a) cause vasodilation, increased vascular permeability & pain.
Lipoxygenase Pathway
and were first isolated
Results in the production of leukotrienes (they have a conjugated triene chain
neutrophils, they are activated by
from leukocytes), and lipoxins (produced mainly as intermediates by
platelet-leukocyte interaction), which have opposing effects.
Leukotrienes :---Exacerbate acute inflammatory response:
potent as histamine)
1. Increased vascular permeability (up to 1000X as
Chemical mediators released during inflammation intensify and propagate the inflammatory response.
A chemical mediator is any messenger that acts on blood vessels, inflammatory cells or other cells to
Contribute to an inflammatory response. Thesce mediators are soluble, diffusible molecules that can act
locally and systemically
AISO called as permeability factors or endogenous mediators of increased vascular permeability, these
are a large and increasing number of endogenous compounds identified which can enhance vascular
permeability. However, currently many chemical mediators have been which partake in other
fever, pain and cause tissue
processes of acute inflammation as well e.g, vasodilatation, chemotaxis,
damage. plasma, or
The substances acting as chemicalmediators of inflammation may be released from the cells, the
damaged tissue itself. They are broadly classified into 2 groups:
i) mediators released by cells
i) mediators originating from plasma.
I. CELL-DERIVED MEDIATORS
1. Vasoactive amines (Histamine, 5-hydroxytryptamine, neuropeptides)
2. Arachidonic acid metabolites (Eicosanoids)
i. Metabolites via cyclo-oxygenase pathway (prostaglandins, thromboxane A2, prostacyclin)
ii. Metabolites via lipo-oxygenase pathway (5-HETE, leukotrienes, lipoxins)
3. Lysosomal components (from PMNs, macrophages)
4.Platelet activating factor
5.Cytokines (|L-1, TNF-a, TNF-B, IFN-Y, chemokines)
6. Free radicals (0xygen metabolites, nitricoxide)
II. PLASMA-DERIVED MEDIATORS (PLASMA PROTEASES):Products of:
1. The kinin system
2. The clotting system
3. The fibrinolytic system
4. The complement system
1) Vasoactive Amines
increased
Histamine and serotonin are believed to be the primary mediators in the immediate active phase of
permeability. Vasoactive amines cause vasodilation and increased vascular permeability by causing
endothelial cells to round up, increasing intercellular gaps, and also increasing vesiculovacuolar transfer of
fluids. Vasoactive amines are stored within cells for immediate release.
Histamine
Extensively distributed in tissues, the main source being the mast cells that are normally present in the
perivascular connective tissue; it is preformed and stored in granules with heparin.
Histamine is important mainly in early inflammatory responses and in type 1 hypersensitivity
reactions.
Histamine is important in the immediate active phase of increased vascular permeability.
It is alsoimportant in allergic reactions as it promotes contraction of extravascular smooth muscles in
the bronchi and stimulates stromal cells to synthesize and release eotaxins (chemotaxins for
eosinophils).
The following agents can stimulate release of histamine from mast cells:
Ag (eg pollen) binding to lgE on mast cells
Anaphylotoxins (C3a and CSa)
, Physical injury, mechanical trauma, heat, chemical agents
Snake venoms, toxins, bile salts, ATP
Histaminc-releasing factors from ncutrophils, monocytes, and platelets
Cytokines (|L-I, IL-8)
Neuropeptides, like substance P
Serotonin
It is present in tissues like chromaffincells of GIT, spleen, nervous tissue, mast cells and platelets.
The actions of 5-HT are similar to histamine but it is a less potent mediator of increased vascular
permeability and vasodilatation than histamine.
Neuropeptides.
" Another elass of vasoactive amines is tachykinin neuropeptides, such as substance P, neurokinin A,
vasoactive intestinal polypeptide (VIP) and somatostatin.
" These small peptides are produced in the central and peripheral nervous systems.
The major proinflammatory actions of these neuropeptides is as follows:
a) Increased vascular permeability.
b) Transmission of pain stimuli.
c) Mast cell degranulation.
2)Arachidonic Acid Metabolites
When cells are activated by diverse stimuli, their lipid membranes can be rapidly remodelled to
generate biologically active lipid mediators.
These lipid mediators are like short-range hormones that are formed rapidly and exert their effects
locally and then are inactivated.
Arachidonic acid is a 20-carbon polyunsaturated fatty acid that is derived directly from the diet or by
conversion from linoleic acid.
Arachidonic acid is not free in the cell but esterified in membrane phospholipids; in order to be
released from phospholipids it must be activated by cellular phospholipases, particularly phospholipase
A2 (via mechanical, chemicaland physical stimuli or by other mediators).
Following activation, biosynthesis of the metabolites of arachidonic acid occurs by one of two major
pathways: the cyclooxygenase pathway and the lipoxygenase pathway.
Cyclooxygenase Pathway
Twoenzymes are able to produce these products: COX-1 and COX-2.
COX-1 is normally present (constitutively expressed) and necessary for everyday activities; also
synthesized at sites of inflammation.
COX-2 is transcriptionally regulated - present in various circumstances (eg inflammation).
The main 3 products resulting from this pathway are:
Thromboxane A2 is found in platelets and other cells is a potent platelet aggregator and vasoconstrictor
Prostacyclin (PG I2) is found predominantly in endothelial cells; a potent inhibitor of platelet aggregation
and vasodilator.
Prostaglandins (PG'sE2, D2, F2a) cause vasodilation, increased vascular permeability & pain.
Lipoxygenase Pathway
and were first isolated
Results in the production of leukotrienes (they have a conjugated triene chain
neutrophils, they are activated by
from leukocytes), and lipoxins (produced mainly as intermediates by
platelet-leukocyte interaction), which have opposing effects.
Leukotrienes :---Exacerbate acute inflammatory response:
potent as histamine)
1. Increased vascular permeability (up to 1000X as
