Chemical Mediators of

Inflammation
and
Systemic Effects of
Inflammation
 Various events in inflammation
are controlled by chemicals.
These are called
Chemical Mediators of Inflammation
(CMOI)

CMOI may be circulating

in plasma and require
activation or they may be
secreted by inflammatory
and other cells.
 Present either
Many cell derived CMOI
in plasma
If remain inactivated – synthesized
Potentially harmful or in cells in response to injury

Properties Plasma COMI are

synthesized in liver
Many act as
opsonins of
CMOI

Enzymatic Preformed cell-

properties derived CMOI are
Have short Histamine
Bind to specific Serotonin
receptors Half life
Lysosomal enzymes
 Chemical Mediators of Inflammation
 Vasoactive amines: Histamine and serotonin
 Plasma proteases: 1. Complement system.
2. Kinin system,
3. Clotting system
 Arachidonic acid metabolites: 1. Prostaglandins
2. Leukotrienes
3. Lipoxins
 Platelet activating factor
 Cytokines and Chemokines
 Nitric Oxide
 Lysosomal enzymes of leukocytes.
 Oxygen derived free radicals.
 Neuropeptides
 Action of Various CMOIs
Histamine

 It is derived chiefly from granules of mast cells and

basophils
 Action: vasodilatation and increased vascular permeability.

Serotonin
 It is derived from platelets. Its role in humans is not well
defined
 Actions: Similar to histamine

Kinin System

 Bradykinin is produced by the action of kallikrein on high

molecular weight kininogen

 Action: Pain, smooth muscle contraction, vasodilatation and

increased vascular permeability
Complement System
 Group of plasma proteins, derived from liver, labeled as C1
to C9.
 Circulate in plasma as inactive precursors. Activation occurs
in a cascading manner.
 Critical event in activation is formation of C3 cleavage
products.
 C3 cleavage can occur by three pathways
 Classical pathway
 Alternate pathway
 Lectin pathway
 Action: Microbial lysis, promotion of phagocytosis, vascular
dilatation, increased vascular permeability.
 Excess complement activity is prevented by natural
inhibitors like DAF and C1INH. (Absence of these inhibitors is
responsible for diseases like PNH and hereditary angioneurotic
 Complement Activation

C5a

Classical
C1
M C3a

LPS
Alternate Cobra venom
polysaccharides
C3b
M
Lectin C1
+ C5b
Plasma
+
MAC
Lectin C6-9
 Arachidonic acid metabolites

• AA is a constituent Disturbed Cell

Membrane
of cell membranes.
• It can be obtained
AA released
through dietary
sources
Metabolized through Metabolized through
OR Cyclooxygenase Lipooxygenase
pathway pathway

• It can be
synthesized in the
body from linoleic PG’s Lipoxins
acid liberated liberated
 PGs have following pro-inflammatory
properties:
• PGD2, PGE2, and PG2α produces vasodilatation.

• PGI2 increases vascular permeability.

• PGE2 produces pain

 Leukotrienes produce following effects:

• LTB4 is a potent chemotactic agent. It also
enhances leukocyte adhesion.

• LTC4, LTD4 and LTE4 cause bronchospasm and

increase vascular permeability.
Platelet Activating Factor
Variety of cells elaborate PAF, important amongst these are mast
cells, neutrophils, macrophages and endothelial cells.

Action: Affects multiple steps of inflammation. It also enhances

synthesis of other CMOIs esp. eicosanoids.

Cytokines and Chemokines

Activated macrophages produce IL-1 and TNFα. T
cells produce TNFß.they have following effects:
Endothelial activation.
Neutrophil priming
Acute phase responses.

Chemokines recruit leukocytes to the site of injury.

Nitric Oxide
• It is produced by endothelial cells, neurons and macrophages.

• Action: It depresses mast cell activity and leukocyte

recruitment. It reacts with oxygen radicals to form
peroxynitrites that have potent anti-microbial effect.

Clotting System

• Platelets, SMCs, ECS, and many other cell types express

receptors called protease activated receptors.

• When thrombin binds to PAR, these cells get activated.

Activated cells show increased expression of adhesion
molecules. Increased production of chemokines and AA
metabolites also takes place.
Lysosomal Enzymes of Leukocytes

• Lysosomes of neutrophils and monocytes contain acid and neutral

proteases, in addition to several other potent enzymes.

• Neutral proteases cleave C3 and activate the kinin system.

• Leakage of these enzymes outside of cell is responsible for damaging

normal tissues during inflammatory response.

Oxygen derived Free radicals

• Effect of free radicals apart from helping in destruction of microorganisms

is:

– Endothelial cell damage – this increases vascular permeability

– Inactivation of anti-proteases.

– Injury to normal cells

 Acute Phase Response
Acute phase response represents systemic
manifestations of acute inflammation. They are also
known as systemic inflammatory response
syndrome (SIRS). Its manifestations are as follows:
Fever, rigor, chills

Leukocytosis

Raised level of acute phase proteins: CRP, Serum

amyloid A (SAA), fibrinogen and many others.

Increased pulse and BP, anorexia, nausea, somnolence

and malaise.

In some instances, septic shock and acute respiratory

distress syndrome.
 Laboratory Findings in Inflammation
Acute Inflammation Chronic Inflammation
1. Changes in peripheral DLC
1. Changes in peripheral DLC
• Absolute neutrophilic
leukocytosis • Absolute monocytosis
• Left shift: > 10% band
forms or presence of 2. Increased serum IgG
earlier precursors.
3. ESR raised (+ to +++)
• Toxic granulation in
neutrophils.
4. CRP raised
2. Increased serum IgM
5. Serum protein electrophoresis
3. ESR may be raised (+)

4. CRP raised • Serum albumin decreased (++)

5. Serum protein electrophoresis • Increased γ -globulin

• Serum albumin decreased
(+)
• Normal γ - globulin