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Inflammation Mediators: A Review

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L.S. Chauhan

L. S. Chauhan

The inflammatory process involves a series of events that can be elicited
by numerous stimuli and provokes a characteristic pattern of responses. At
a microscopic level, the familiar clinical signs of erythema, edema, tenderness,
and pain usually accompany the response.

A substance that causes one of the component events in inflammation through
a specific receptor is called a mediator of inflammation. Both endogenous
and exogenous substances may acts as mediators e.g. proteins, lipids, histamine,
serotonin, nitric oxide, endotoxin, interleukins, tumor necrosis factors etc.

Introduction

When tissue injury occurs, whether caused by bacteria, trauma, chemicals, heat
or any other phenomenon, the injured tissues release multiple substances that
cause dramatic secondary changes in the tissues. The entire complex of tissue
changes is called inflammation.

Inflammation
is characterized by (1) vasodilation of the local blood vessels with consequent
excess local blood flow; (2) increased permeability of the capillaries allowing
leakage of large quantities of fluid into the interstitial space; (3) often
clotting of the fluid into the interstitial space because of excessive amounts
of fibrinogen and other proteins leaking from the capillaries; (4) migration of
large numbers of granulocytes and monocytes into the tissue; and (5) swelling
of the tissue cells. Some of the many tissue products that cause these
reactions are histamine, bradykinin, serotonin, prostaglandins, reaction
products of the complement system, reaction products of the blood-clotting
system, and multiple substances called lymphokines that are released by
sensitized cells1.

Each type of stimulus provokes a characteristic pattern of response. At a
macroscopic level, the familiar clinical signs of erythema, edema, tenderness
and pain usually accompany the response. Inflammatory responses occur in the
three distinct phases, each apparently mediated different mechanisms: (1)
an acute transient phase, characterized by local vasodilation and increased
capillary permeability; (2) a delayed, sub acute phase, most prominently characterized
by infiltration of leukocytes and phagocytic cells; (3) a chronic proliferative
phase, in which tissue degeneration and fibrosis occur. Many different mechanisms
are involved in the inflammatory process2, 3. `Walling-off’ Effect
of Inflammation. One of the first results of inflammation is to `wall-off’
the area of injury from the remaining tissues. Fibrinogen clots block the
tissue space and the lymphatic in the inflamed area so that after a while
fluid rarely flows through the spaces. This walling-off process delays the
spread of bacteria or toxic products.

Responses During Inflammation.

Tissue Macrophage

Within
minutes after inflammation begins, the macrophages already present in the
tissues, whether histiocytes in the subcutaneous tissues, alveolar macrophages
in the lungs, microglia in the brain or others, immediately begin their
phagocytic actions. When activated by the products of infection and
inflammation, the first effect is rapid enlargement of each of these cells.
Next, many of the previously sessile macrophages break loose from their
attachments and become mobile, forming the first line of defense against
infection during the first hours or so1.

Neutrophil Invasion

Within
the first hour or so after inflammation begins, large numbers of neutrophils
begin to invade the inflamed area from the blood. This is caused by products
from the inflamed tissues that initiate the following reaction;(1) they alter
the inside surface of the capillary endothelium, causing neutrophils to stick
to the capillary walls in the inflamed area. This effect is called margination;
(2) they cause the endothelial cells of the capillaries and small venules to
break away from each other easily, allowing opening large enough for
neutrophils to pass by diapidesis directly from the blood into the tissue
space; (3) other products of inflammation cause chemotaxis of the neutrophils
toward the injured tissues1, 4.

Thus
the inflamed area becomes well supplies with neutrophils. These neutrophils
begin immediately their scavenger functions for killing bacteria and removing
foreign matter.

Acute
increase in neutrophils in the blood -`Neutrophilia’. Within a few hours after
the onset of acute, severe inflammation, the number of neutrophils in the blood
sometimes increases four to five folds i.e. from a normal of 4000 to 5000 to
15000 to 25000 neutrophils per micro liter.

A Second Macrophage

With
the invasion of neutrophils, monocytes from the blood enter the inflamed tissue
and enlarge to become macrophages. The build up of macrophages in the inflamed
tissue area is much slower than neutrophils, requiring several days to become
effective. After several days to several weeks, the macrophages finally come to
dominate the phagocytic cells of the inflamed area because of greatly increased
bone marrow production of monocytes1, 4.

Granulocytes and Monocytes.

The
increased production of both granulocytes and monocytes by the granulocytic and
monocytic progenitor cells of the marrow. It takes 3 to 4 days before newly
formed granulocytes and monocytes reach the stages of leaving the bone marrow.

Mediators of inflammation

A substance that causes one of the component events in inflammation through
a specific receptor is called a mediator of inflammation. Both endogenous
and exogenous substances can satisfy the definition.

Acute Inflammation: mediators are derived from plasma

Proteins (Enzyme cascades)

 Complement
system

 Coagulation system

 Fibrinolytic system

 Kinin
system

Lipids

 Eicosanoids

 Platelet
Activating Factor

Other

 Histamine

 Serotonin

 Nitric
Oxide

 Endotoxin

Chronic Inflammation

 Cytokine Proteins

 Interleukin-1

 Interleukin-6

 Tumor Necrosis Factor-a    

Complement system:

The complement
system is a cascade system of enzymatic proteins. It can be activated during
the acute inflammatory reaction in various ways:

In tissue
necrosis, enzymes capable of activating complement are released from dying
cells. During infection, the formation of antigen-antibody complexes can
activate complement via the classical pathway, while the endotoxins of
Gram-negative bacteria activate complement via the alternative pathway.
Products of the kinin, coagulation and fibrinolytic systems can activate
complement5. The products of complement activation most important in
acute inflammation include:

C5a:
chemotactic for neutrophils; increases vascular permeability; releases
histamine from mast cells

C3a:
similar properties to those of C5a, but less active

C567:
chemotactic for neutrophils

C56789:
cytolytic activity

C4b, 2a, 3b:
opsonisation of bacteria (facilitates phagocytosis by macrophages).

Coagulation system.

The coagulation
system is responsible for the conversion of soluble fibrinogen into fibrin, a
major component of the acute inflammatory exudates6, 7. Coagulation
factor XII (the Hageman factor), once activated by contact with extracellular
materials such as basal lamina, and various proteolytic enzymes of bacterial
origin, can activate the coagulation, kinin and fibrinolytic systems.

Fibrinolytic system.

Plasmin is
responsible for the lysis of fibrin into fibrin degradation products, which may
have local effects on vascular permeability8.

Kinin system.

The
kinins are peptides of 9-11 amino acids; the most important vascular
permeability factor is bradykinin9. The kinin system is activated by
coagulation factor XII10, 11. Bradykinin is also a chemical mediator
of the pain, which is a cardinal feature of acute inflammation12.

Eicosanoids:

They
are generated from phospholipids in response to a wide range of different
stimuli, and their presence has been detected in every tissue in the body. The
control of many physiological process and are the most important mediators and
modulators of the inflammatory action13, 14.

Platelet Activating Factors:

 Newly defined class of biologically active
lipids, which can produce effects at low concentrations. PAF has actions on the
variety of different target cells and is believed to an important mediator in
both acute and persisting allergic and inflammatory phenomena15, 16.

Histamine:

 This is the best-known chemical mediator in
acute inflammation. It causes vascular dilatation and the immediate transient
phase of increased vascular permeability17. It is stored in mast
cells, basophil and eosinophil leukocytes, and platelets. Histamine release
from those sites (for example, mast cell degranulation) is stimulated by
complement components C3a and C5a, and by Iysosomal proteins released from
neutrophils.

Serotonin (5-hydroxytryptamine):

 This is present in high concentration in mast
cells and platelets. It also may play a role in mediating inflammation, but
their antagonists ameliorate only certain types of inflammatory responses18.

Endotoxin:

 Bacterial products and toxins can act as
exogenous mediators of inflammation i.e. endotoxin, or LPS of Gram-negative
bacteria. The immune system of higher organisms has probably evolved in a
veritable sea of endotoxin, so it is perhaps not surprising that this substance
evokes powerful responses19. For example, endotoxin can trigger
complement activation, resulting in the formation of anaphylatoxins C3a and
C5a, which cause vasodilation and increase vascular permeability. Endotoxin
also activates the Hageman factor, leading to activation of the coagulation and
fibrinolytic pathways as well as the kinin system. In addition, endotoxins
elicit T cell proliferation, and have been described as super antigen for T
cells.

Nitric Oxide:

 Formed from the amino acid arginine by nitric
oxide syntheses present in endothelium (constitutive) and macrophages
(inducible). Many of the long-lived actions of nitric oxide in vivo appear to be caused by stable
S-nitro so compounds (R-SNO) Actions of nitric oxide are vasodilator, anti-platelet
aggregation, cytotoxic/antimicrobial20,21.

Cytokines

Cytokines are proteins that are secreted by various types of immune cells and
serve as signaling chemicals22. The central role of cytokines is
to control the direction, amplitude, and duration of the inflammatory response.

There are two main groups of cytokines: pro-inflammatory and anti-inflammatory.
Pro-inflammatory cytokines are produced predominantly by activated immune
cells such as microglia and are involved in the amplification of inflammatory
reactions. Anti-inflammatory cytokines are involved in the reduction of inflammatory
reactions.

Interleukin-1
(IL-1)

Macrophages
and monocytes are the main source of this cytokine. IL-1 has both Paracrine
effects on cells in the vicinity23, 24,25,26.

®Causing
them to produce tissue factor and thus triggering the blood-clotting cascade.

®Stimulating
the synthesis and secretion of a variety of other interleukins.

®Helping
to activate T cells and thus initiate an adaptive immune response.

Hormonal effects as it is carried in the blood throughout the body.

®Decreasing
blood pressure.

®Inducing
fever.

IL-1 causes fever by stimulating
the release of prostaglandin’s,
which act on the temperature control center of the hypothalamus.

Tumor
Necrosis Factor-alpha (TNF-α)

Large amounts of TNF-α are quickly released by stimulated mast cells.
All the cells involved in inflammation have receptors for TNF-α, and
are activated by it to synthesize more on their own. This positive feedback
quickly amplifies the response23,24,27.

References:

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About Authors:

*L. S. Chauhan, C. S. Chauhan, C. P. Jain

B. N. College of Pharmacy, Udaipur, Rajasthan – 313001.

Dept. of Pharmaceutical Sciences, M.L.S.University, Udaipur, Rajasthan –
313001,

e-mail: lalit_cology@rediffmail.com

L.S. Chauhan

*L. S. Chauhan1

*Mr. L.S. Chauhan: is Reader in Pharmacology at Bhupal Nobles’
College of Pharmacy, Udaipur-313 002 (Rajasthan), with 10 years of teaching
and research experience. He has supervised 1 M. Pharm. thesis and has publications
in international and national journals of repute. His area of research includes
Phytochemical screening and plant biotechnology. He is executive member of
APTI (Rajasthan State Branch). He is registered for Ph.D. at M.L.S. University,
Udaipur, and Rajasthan, India.
Email address: lalit_cology@rediffmail.com
*Corresponding author

C. S. Chauhan

Mr. C.S. Chauhan is presently working as a Reader in Pharmaceutics
at B.N. College of Pharmacy, Udaipur with 5 years of teaching experience and
is registered for Ph.D. at M.L.S. University, Udaipur.

C. P. Jain

Dr.C.P. Jain: is Professor in Pharmaceutics at Dept. of Pharmaceutical
Sciences, M.L.S.University, Udaipur. He has supervised number of M. Pharma
thesis and currently seven research scholars are doing their Doctorate under
his able guidance. His area of research includes novel drug delivery systems
and analytical method development. Dr. Jain has number of national and international
research to his credit.

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