CHEMICAL MEDIATORS OF

ACUTE INFLAMMATION
 Definition:
 Any messenger that acts on blood
vessels, inflammatory cells, or other cells
to contribute to an inflammatory
response.
 They are inactive precursors that are
activated at the site of inflammation
 Mediators may be produced by cells at
the site of inflammation or they may be
synthesized by the liver.
 Mediators can be
 A. Cell derived mediators:
 B. Plasma protein derived mediators:
 A. Cell derived mediators:
 Cells from which the mediators are
derived include.
 1.Tissue macrophages
 2. Mast cells
 3. Endothelial cells
 4. Leukocytes recruited to site of
inflammation
The mediators produced by these cells
are.
1.Vasoactive amines
2.Arachidonic acid metabolites.
3.Platelet activating factor.
4.Cytokines.
5.Chemokines
6.Free radicals (ROS and NO)
7.Lysosomal components.
 B. Plasma derived mediators:
1. Complement system
2. The Kinin system
3.The clotting system
4.Fibrinolytic system
 1. Vasoactive Amines:

 a. Histamine:

 Histamine is produced by many cells,

particularly mast cells adjacent to

vessels, as well as circulating basophils
and platelets.
 Histamine is released from mast cell
granules in response to a variety of
stimuli:
(1) Physical injury such as trauma, cold or
heat
(2) Immune reactions involving binding
of IgE antibodies to mast cells
(3) C3a and C5a fragments of complement
(4) Neuropeptides (e.g. substance P)
(5) Certain cytokines (e.g. IL-1 and IL-8).
 Functions:
 Histamine causes arteriolar dilation and
vascular permeability.
 It does so by inducing
 Venular endothelial cells contraction
leading to increase in Interendothelial
gaps.
 Soon after its release, histamine is
inactivated by histaminase.
 Serotonin (5-hydroxytryptamine):
 It is also a preformed vasoactive
mediator with effects similar to those of
histamine.
 It is found primarily within platelet .
 It is released during platelet aggregation.
2.Arachidonic Acid (AA) Metabolites:
 They are Prostaglandins, Leukotrienes,
and Lipoxins.
 Also called Eicosanoids
 They can mediate virtually every step of
inflammation.
 Leukocytes, mast cells, endothelial cells,
and platelets are the major sources of
AA metabolites in inflammation.
 AA is a 20-carbon fatty acid and present
in the body mainly as a component of cell
membrane phospholipids
 It is released from these phospholipids
due to cellular phospholipases.
 Phospholipases are activated by
mechanical, chemical, or physical stimuli,
or by inflammatory mediators such as
C5a.
 AA metabolism proceeds along one of two
major enzymatic pathways.
 1. Cyclooxygenase pathway
 2. Lipoxygenase pathway
 Cyclooxygenase pathway:
 Cyclooxygenase (COX) is an enzyme that
acts on arachidonic acid to Produce
prostaglandin E2 (PGE2), PGF2, PGD2,
PGI2 (prostacyclin), and thromboxane A2
(TXA2).
 PGD2 is the major metabolite of the
cyclooxygenase pathway in mast cells.
 Along with PGE2 and PGF2 it causes
1. Vasodilatation
2. Edema formation.
3. Fever
4. Pain
 Lipoxygenase pathway:
 5-Lipoxygenase is the predominant AA-
metabolizing enzyme in neutrophils.
 It acts on Arachidonic acid and convert it

into Leukotriens which include LTA4,

LTB4,LTC4,LTD4 and LTE4.
 Leukotriens cause.

1.Chemotacxis
2.Vasoconstriction
3.Increase vascular permeability
4.Brochospasm.
 Lipoxins are produced by Arachidonic acid
due to action of 12-lipoxygenase enzyme.
 Lipoxins function mainly as inhibitors of
inflammation.
 They actually inhibit neutrophil
chemotaxis and their adhesion to
endothelium.
 Important lipoxins include Lipoxin A4 and
Lipoxin B4
3.Platelet-Activating Factor:
 Platelet-activating factor (PAF) is another
phospholipid-derived mediator.
 PAFis generated from the membrane
phospholipids of neutrophils, monocytes,
basophils, endothelial cells, and platelets
by the action of phospholipase A2.
 It
stimulates platelets, causes
vasoconstriction and bronchoconstriction
4.Cytokoines:
 Cytokines are polypeptides that are

produced by many cell types.

 They function as mediators of

inflammation and immune response.

 Important cytokines are Interleukines

(abbreviated as IL and numbered like

IL1, IL2 etc) and Tumor Necrosis factor
 Out of these main cytokines are IL1 and

TNF
 TNF and IL-1 are produced by activated
macrophages, as well as mast cells,
endothelial cells, and some other cell
types.
 Their secretion is stimulated by microbial
products, immune complexes, and
products of T lymphocytes produced
during immune processes.
 Functions of IL-1 and TNF : The principal
role of these cytokines is endothelial
activation.
 Both TNF and IL-1 stimulate the
expression of adhesion molecules on
endothelial cells.
 This causes increased leukocyte binding
and recruitment
 They in turn enhance the production of
additional cytokines notably chemokines
 IL-1 activates tissue fibroblasts, resulting
in increased proliferation and production
of ECM.
 Although TNF and IL-1 are secreted by
macrophages and other cells at sites of
inflammation, they may enter the
circulation and act at distant sites to
induce the systemic acute-phase reaction.
 It is often associated with infection and
inflammatory diseases.
 The features of it are.

1.Fever
2.Lethargy
3.Cachexia
4.Hepatic synthesis of acute phase
proteins
5.Neutrophil release into circulation
6.Release of ACTH
5.Chemokines:
 Proteins in nature and produced by

macrophages and activated leukocytes.

 They help in chemotaxis and leukocyte

activation
 About 40 different chemokines have been

identified.
 Classified into four types

1. α chemokines)

2. β chemokines)

3. γ chemokines)

4. CX3 chemokines
6.Free radicals:
a. Reactive Oxygen Species:
 Reactive Oxygen Species (ROS) are
synthesized via the NADPH oxidase
pathway and are released from
neutrophils and macrophages after they
are activated by microbes, immune
complexes etc.
 They include superoxide(0.-2) Hydrogen
peroxide(H2o2) and OH-
 When the ROS are produced within
lysosomes they function to destroy
phagocytosed microbes and necrotic
cells.
 When secreted at low levels, ROS can
increase levels of chemokines and
cytokines.
 At higher levels, these mediators are
responsible for
 Endothelial cell damage and therefore
increased vascular permeability.
 b. Nitric oxide:
 NO is a short-lived, soluble, free-radical gas
produced by many cell types
 NO is synthesized de novo from L-arginine,
molecular oxygen, and NADPH by the enzyme
nitric oxide synthase (NOS).
 NO plays many roles in inflammation.
1. Relaxation of vascular smooth muscle
(vasodilation).
2. Antagonism of all stages of platelet activation
(adhesion, aggregation, and degranulation)
3. Reduction of leukocyte recruitment at
inflammatory site
4. Act as a microbicidal agent in activated
macrophages.
7.Lysosomal enzymes:
 They are proteolytic enzymes.

 Play role in microbial killing and tissue

injury.
 Main enzymes include collagenase,

elastase and cathepsin.

8.Neuropeptides:
 These are small proteins, such as
substance P and neurokinin A.
 They are produced in central and
peripheral nervous systems.
 They transmit pain signals, regulate vessel
tone, and modulate vascular permeability.
 B. Plasma Protein-Derived Mediators
 A main event in the generation of several
circulating mediators of inflammation is
activation of Hageman factor.
 Activated Hageman factor (factor XIIa) initiates

four systems involved in the inflammatory

response
1. Complement system
2. Kinin system
3. Clotting system
4. Fibrinolytic system
1.Complement:
 It is a complex of 20 plasma proteins and their
cleavage products.
 Its components C1-C9 are present in inactive form
in plasma.
 They are activated by cleavage in a cascade
pattern
 The most important step is the activation of C3
component.
 There are three pathways for the activation of C3.
1. Classical Pathway
2. Alternate Pathway.
3. Lectin Pathway
a. Classical pathway
 Commenced by
fixation of the first
complement
component C1 to
antigen-antibody
complexes.
 The C1 becomes
activated.
 The C1 activates 2
other complement
proteins, C2 and C4
by cutting them in
half.
 C3 Convertase
 Each component
forms two
components a and b.
 C2a and C4a diffuse
away
 C4b and C2b bind to
form C3-convertase.
 C3 convertase then
acts on C3 to produce
C3a and C3b.
 The Alternative pathway
 C3 contains an unstable
bond.
 This unstable bond causes
slow spontaneous break
down of C3 to C3b and C3a
 C3b on the surface of a
pathogen binds to another
plasma protein called factor
B. This complex binds to
Factor D resulting in the
formation of C3 convertase
of alternate pathway.
c. Lectin pathway:
 In which a plasma Manose binding lectin
(Carbohydrate-binding protein)binds to
mannose residues on microbes and then
activates C1, an early component of the
classical pathway but in the absence of
antibodies.
 From onwards the pathway joins the classical
one
 All three pathways lead to the formation of
C3 convertase which cleaves C3 into C3a and
C3b.
 The fate of C3b is to bind to the C3 convertase
complex to form C5 convertase.
 C5 convertase cleaves C5 to generate C5a and
C5b and initiate the final stages of formation
of C6 to C9.
 C5-C9 are together called membrane attack
complex.
 Functions of complement can be
discussed as
1.Membrane Attack Complex (MAC)
induced lysis:
 This complex causes punch holes in the

membranes of microbes.
2.Complement fragments induced
funtions:
a.C3a and C5a (Anaphylatoxins) cause
release of histamine from mast cells
and therefore cause vasodilatation.
b.C5a activates Lipoxygenase pathway and thus
increase the production of leukotriens.
c.C3b opsonizes the microbes.
d.C5a is itself a powerful chemoattractant.
 The activation of complement is tightly

controlled by cellular and circulating regulatory

proteins.
 The presence of these inhibitors protects
normal cells from inappropriate damage during
protective reactions against microbes.
2.Kinin system:
 The end product of this system is

Bradykinin which is derived from HMWK.

 Bradykinin has following actions

1.Smooth muscle contraction

2.Vasodilation
3.Increased vascular permeability
4.Pain
3.Clotting system:
 The activated Hageman factor( Factor

XIIa) leads to formation of fibrinogen

 Thrombin acts upon fibrinogen to produce
Fibrin and fibrinopeptides.
 Fibrinopeptides perform following

functions
1.Increased vascular permeability
2.Chemotaxis of leukocytes
3.Anti coagulant activity
4.Fibrinolytic system:
 It involves the breakdown of plasminogen

in presence of kallikrein to produce

plasmin. Plasmin then
 Acts on Fibrin to yield FDPs
 Plays a role in activation of complement.
 It causes conversion of C3 to C3a
 SUMMARY
 Cell-derived Mediators of Inflammation:
 Vasoactive amines:
 Histamine and serotonin:
 Main effects are vasodilation and
increased vascular permeability
 Arachidonic acid metabolites:
 Prostaglandins, leukotrienes and lipoxins:
 They mediate almost every step of
inflammation.
 Lipoxins are antagonists to them, they
inhibit neutrophil chemotaxis
 Cytokines: Proteins produced by many
cell types.
 Main ones are IL1 and TNF
 They produce acute phase reaction.
 Chemokines:
 Chemotaxis and leukocyte activation.
Reactive oxygen species:
 Have role in microbial killing, tissue injury
 Nitric oxide: Vasodilation, microbial killing
 Lysosomal enzymes: Role in microbial
killing, tissue injury
 Plasma Protein-Derived Mediators
 Complement proteins:
 Activation of the complement system by
microbes or antibodies leads to the
generation of multiple breakdown
products, which are responsible for
leukocyte chemotaxis, opsonization and
phagocytosis and killing of microbes and
other particles.
 Coagulation proteins:
 Activated factor XII triggers the clotting,
kinin and complement cascades, and
activates the fibrinolytic system.