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Chemical mediators of inflammation

Prof. Chandu de Silva


Department of Pathology
Faculty of Medicine, Colombo

Chemical mediators
1. Chemical mediators may be circulating in plasma or
may be produced locally at the site of inflammation
by cells.
2. Most mediators induce their effects by binding to
specific receptors on target cells.
3. Mediators may stimulate target cells to release
secondary effector molecules.
4. Mediators may act only on one or a few targets or
may have widespread activity.

Chemical mediators
5. Mediator function is tightly regulated.
Once activated and released from the
cell, most mediators quickly decay, are
inactivated by enzymes, eliminated or
are inhibited.
6. A major reason for the checks and
balances is that most mediators have
the potential to cause harmful effects.

CHEMICAL MEDIATORS OF INFLAMMATION


Originating from cells

Present in Plasma

Performed

Newly Synthesized

1) Amines-Histamine

1) Arachidonic acid

Serotonin
2) Lysosomal
enzymes

metabolites
2) Cytokines
3) Platelet activating
factor
4) Nitric oxide

1) Complement
system
2) Kinin system
3) Clotting /
Fibrinolytic
systems

Complement system
Has 20 component proteins, together
with their cleavage products.
Mediate biologic reactions, all of which
serve in the defense against microbial
agents.

CLASSICAL PATHWAY

ALTERNATE PATHWAY

Ag-Ab complexes bind to C1

C3

Activated C1
C4+C2

Bacterial endotoxins,
Aggregated globulins

direct cleavage by
plasmin, bacterial
proteases

C3 Convertase
(C4b2a)
Increase Vascular
permeability
Vasodilation

C3a

C3b

C3 C3b
C3bBb (C3
convertase)

C5
C3bBb3b (aternate
path C5 convertase)

C5 convertase classical
Pathway (C4b2a3b)

Chemotaxis
Adhesions of
leukocytes
to endothelium

C5a

C5b

C5b67

Chemotaxis

C5b-9 (Membrane
attack complex)

Leukocyte
activation
Membrane lysis
Activate Arachidonic of cells
Acid pathway

Productionof
oxygen
metabolites

Complement system
C3b acts as an opsonin.
C3 and C5 can be activated by several
proteolytic enzymes present in the
inflammatory infiltrate (plasmin,
lysoxmal enzymes).

CLOTTING FIBRINOLYTIC SYSTEM


Hageman factor (Factor XII)
Negatively changed surfaces
(collagen, basement membrane)
Cofactor HMWK
(high molecular weight
kininogen)

Activated Hageman Factor


(Factor XIIA)

KININ SYSTEM

CLOTTING SYSTEM

FIBRINOLYTIC SYSTEM

KININ SYSTEM
Prekalikrenin

Kalikrein

Chemotaxis
Converts C5toC5a

Highmolecular
Weight kininogen
(HMWK)

Bradykinin

Increase vascular permeability


Pain
Dilatation of blood vessels
Contraction of smooth muscle

FIBRINOLYTIC SYSTEM
Plasminogen

Plasmin

Lyse fibrin clots


Increase vascular
permeability

Activates factor XII


Cleaves C3 to produce C3 fragments
Degrades fibrin to fibrin split products

CLOTTING SYSTEM
XI

XIA

XA

Prothrombin
Fibrinogen

Thrombin
Fibrin

Fibrinopeptides
Increase vascular permeability
chemotaxis

leukocyte
adhesion
fibroblast
proliferation

ARACHIDONIC ACID METABOLISM


Arachidonic acid metabolites are also called eicosanoids.
Cell membrane phospholipids
Phospholipase
Blocked by
corticosteroids

Chemical, physical &


other mediators like C5a
Arachidonic Acid

Cyclooxygenase
pathway

Lipoxygenase
Pathway

Cyclooxygenase pathway
Arachidonic Acid
Blocked by aspirin/
Indomethacin, COX-1 &
COX-2 inhibitors

O2
PGG2
PGH2+(OX) Free
radical of oxygen
Prostacyclin
PGI2

Inhibitor of platelet
aggregation
Vasodilatation
Potentiate oedema

ThromboxaneTXA2

PGE2

Vasoconstriction
Platelet aggregation

PGF2

pain + fever
vasodilatation
Potentiate
oedema

PGD2
Major metabolite in mast
cells, causes vasodilatation

Lipoxygenase Pathway
O2

Lipoxin A4 & B4
Vasodilatation
Inhibit chemotaxis
5HPETE

HETE

Leukotriene
LTA4
LTC4
LTD4
LTE4

LTB4

Chemotaxis
Vasoconstriction
Bronchoconstriction
Vascular Permeability

HPETE = Hydroperoxy eicosatetraenoic


acid
HETE = Hydroxy eicosaaatetraenoic acid
SRS A is a mixture of LTC4 & LTD4

Prostaglandins
Are best regarded as autocoids or local short range
hormones, which are formed rapidly, exert their
effects locally and decay spontaneously or are
destroyed enzymatically.
Prostaglandins also cause pain & fever.
Arachidonic acid metabolites can pass from one cell
to another
Different cells cooperate with one another to produce
different eicosanoids

Cyclooxygenase pathway
There are two forms of cyclooxygenases called
COX-I and COX-2.
COX-1 is found in the gastric mucosa and
mucosal prostaglandins produced by COX-1
are protective against acid induced damage.
Thus inhibition of cyclooxygenase by aspirin
and NSAIDs predisposes to gastric ulceration.
To prevent this highly selective COX-2
inhibitors are now available

Histamin and serotonin


Histamin is present in basophils, platelets and mast cells.
It is released in response to
a variety of stimuli such as
1. Leukocyte derived histamine release factors
2. Physical agents
3. Immunologic reactions
4. C3a, C5a
5. Cytokines

Histamin and serotonin


Histamine causes vasodilatation and is the
principal mediator of immediate phase
reaction.
It is inactivated by histaminase.
Serotonin is found within platelets.
It is released during platelet degranulation
and has actions similar to histamine.

Lysosomal constituents
1.Cationic proteins

Increase vascular permeability


Chemotaxis of monocytes
Inhibition of movement of neutrophils
and eosinophils

2.Acid proteases

Degrade bacteria and debris within


phagolysosomes

3.Neutral proteases

Degrade extracellular components

(eg; elastase, collagenases,

Cleave C3 and C5 directly

cathepsin)

Neutral proteases
These harmful proteases are held in check by
a system of antiproteases in serum and
tissue fluids
eg;

alpha-1 antitrypsin inhibits neutrophil

elastase.
Deficiency of alpha-1 antitrypsin lead to
sustained activity of leukocyte proteases.

Platelet activating factor [PAF]


1.Sources
Mast cells/Basophils
Neutrophils
Monocytes/Macrophages
Endometrium, Platelets

Platelet activating factor [PAF]


Functions
Platelet activation,
Release of histamine from platelets
Increase vascular permeability
Vasoconstriction, bronchoconstriction
Increased leukocyte adhesion to endothelium
Leukocyte degranulation
Stimulates synthesis of other mediators like eicosanoids
Chemotaxis

Cytokines
Cytokines are polypeptide products of activated
lymphocytes (lymphokines) and monocytes (monokines).
Many non lymphoid cells too produce these.
Their secretion is transient and tightly regulated
Their effects tend to be pleiotrophic (different cells are
affected differently by the same cytokine).
They can act on the same cell that produces them
(autocrine effect), on other cells in the immediate vicinity
(paracrine effect) or systemically (endocrine effect).

Types of cytokines
1. Those

regulating

lymphocyte

function

such

as

activation, growth and differentiation.


e.g.-

IL-2-stimulates

lymphocyte

growth

and

transforming growth factor inhibit lymphocyte


growth
2. Cytokines involved in innate immunity- TNF and IL-1
3. Cytokines that activate inflammatory cellsduring cell
mediated immune responses, such as interferon
(IFN- ) and IL-12

Types of cytokines
4. Chemokines that have chemotactic
activity for various leukocytes.
5. Cytokines that stimulate
haematopoiesisGranulocyte-monocyte colony stimulating
factor (GM-CSF) and IL-3

Endotoxin, Bacterial products, immune complexes, toxins,


physical injury, other cytokines

Autocrine, paracrine
& endocrine effects

Acute phase
reactions

Macrophage (and other cell)


activation
IL-I/TNF (Interleukion 1, &
Tissue Necrosis Factor act
synergistically)

Endothelial
effects

Leukocyte
effects

Fibroblast
effects

Acute phase reactions


1. Fever
2. Increased sleep
(slow wave sleep)
3. Decreased appetite
4. Increased synthesis of acute phase proteins
5. Haemodynamic effects
decrease vascular resistance, hypotension,
shock, increase heart rate
3. Neutrophilia
4. Release of ACTH & Corticosteroids

Endothelial effects
1. Leukocyte adhesion
2. Stimulation of PAF
3. Increase procoagulant activity
decrease antico-agulant activity of
endothelium making it potentially
thrombogenic.

Leukocyte effects
Increase cytokine secretion
(IL-1,IL-6)

Fibroblast effects
Collagen synthesis
Proliferation of fibroblasts, release of proteolytic
enzymes by mesenchymal cells

Nitric oxide (NO)


NO is a short lived, soluble free radical gas produced
by endothelial cells, macrophages and specific
neurones in the brain
Causes vascular smooth muscle relaxation.
Antagonism of platelet aggregation and adhesion.
Reduction of leukocyte recruitment at inflammatory sites.
Cytotoxic to certain microbes and tumour cells.
Uncontrolled NO production by activated macrophages in
septic shock can lead to massive peripheral vasodilatation
and shock.

Oxygen derived free radicles


These include superoxide , OH, H2O2 . Their production is
dependent on the activation of the NADPH oxidative
system
They are released by neutrophils and macrophages
They cause,
1. Endothelial cell damage
2. Increase vascular permeability
3. Inactivation of antiproteases, and activation of proteases
4. Injury to other cell types tumour cells, red cells,
parenchymal cells

Serum, tissue fluids and target cells


possess
anti oxidant protective mechanisms
Eg.
ceruloplasmin
transferin
superoxide dismutase
catalase
glutathione peroxidas

Summary of chemical mediators of inflammation


1. Vascular permeability Histamine
C3a, C5a
Bradykinin
Leukotrienes-LTD4,LTC4,LTE4
Platelet activating factor
2. Chemotaxis

C5a
LTB4
Bacterial products, chemokines
(IL-8)

3. Acute phase reactions IL-1,TNF

4.

Tissue destruction

Lysosomal products,O2
derived free radicles, NO

5.

Vasodilatation

Prostaglandins, NO

6.

Fever

IL-1, IL-6,TNF,prostaglandins

7.

Pain

Prostaglandin, Bradykinin

The different mediator systems although discussed separately are


intimately intertwined and act together

With all the mediators, there seems to be an intelligent system of


checks and balances

Systemic effects of inflammation


1) Fever

Infections, toxins
Immune complexes, neoplasia,
IL-1/TNF

IL-6

Vascular receptors in the thermoregulatory


center of the hypothalamus
Prostoglandins (E)
Vasomotor center
Sympathetic nerve stimulation
Vasoconstriction of skin vessels
Reduced heat dissipation
fever

Systemic effects of inflammation


2. Leukocytosis
usually in infflammation - 15,000 to 20,000
cells/ml
in leukemoid reactions 40,000 to 100,000
cells/ml
IL-T/TNF accelerate release of cells from
bone marrow. This leads to a rise in number of
more immature neutrophils in the blood ( shift to
the left).

CSF (colony stimulating factor) causes


proliferation of precursors in bone marrow
Most bacterial infections

neutrophilia.

Infectious mononucleosis and mumps


lymphocytosis.
Parasitic infestations
Typhoid and viral infections

eosinophelia
leucopenia

3.

Acute phase reactions

Increase in slow- wave sleep

Decreased appetite

Hypotension

Increased degradation of proteins

Synthesis of acute phase proteins by the liver


C reactive protein
Serum amyloid A
Complement
Coagulation proteins

Most of these are mediated by IL-1, IL-6 and TNF

Diagnosis of acute
inflammation
Biopsy
Feve
r
Inflammatory
mediators

Cardinal
features of
inflammati
on
Culture, gram
stained smears

ESR
Examination
of
inflammatory
exudate

Inflammat
ory
reaction
Tests for
specific
aetiologica
l factors
Serum antibody levels,
complement levels

Measurement of Creactive protein

Increase of certain
plasma proteins
(C-reactive protein,
fibrinogen,
haptoglobulin)
Increase in total
number of
neutrophils in
peripheral blood
Presence of toxic
granules

Presence of
immature band
forms (shift to
the left)