This document summarizes inflammation and the inflammatory response. It describes inflammation as the body's protective response to injury or infection that involves redness, swelling, heat, and pain. There are two main types of inflammation - acute and chronic. Acute inflammation is short-lived while chronic inflammation can last for months or years. The document then outlines the events in the inflammatory response, including the release of inflammatory mediators, vascular changes, recruitment of phagocytic cells, vasodilation, exudation and edema formation, and cell emigration. Key pro-inflammatory and anti-inflammatory cytokines involved in regulating inflammation are also discussed.
3. INTRODUCTION
Inflammation is the process by which the body deals with
an insult from physical or chemical agents and invasion by
microbes. It is recognized by its cardinal signs, including
redness, heat, swelling and pain.
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TYPES OF INFLAMMATION
ACUTE INFLAMMATION
It is generally of short duration lasting from minutes to a
few days, and is the result of an initial response by cells
of the immune system(primarily PMNs) to remove an
infectious agent.
CHRONIC INFLAMMATION
It may last months to years, and usually results from the
persistence of a microbe in a viable or inert state and
involves lymphocytes, macrophages and plasma cells of
the immune system.
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SIGNS OF INFLAMMATION
Inflammation is a local protective response which is initiated
when there is damage to tissues caused by a cut, burn, or
infection and other causes also. A series of events are
activated which help to recruit various defensive cells and
molecules to the infected/ injured site.
Various signs of inflammation are;
• Redness (Rubor)
• Swelling (Tumor)
• Heat (Calor)
• Pain (Dolor)
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EVENTS OF INFLAMMATION
Release of inflammatory mediators
These are substances released from damaged host cells,
mast cells, leukocytes, and other auxiliary cells. They also
include complement breakdown products and those
products called anaphylatoxins(C3a, C4a, C5a).
Inflammatory mediators can diffuse away from the site of
release due to their small size establishing a concentration
gradient. This concentration gradient is important for
drawing neutrophils from the blood to the infected site.
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Cytokines involved in Inflammation
There are several cytokines that play a role in
inflammation. Cytokines are small proteins released by
various cells in the immune system that act as chemical
messengers, regulating immune responses and
inflammation.
Tumor Necrosis Factor-alpha (TNF-alpha): TNF-alpha is
a pro-inflammatory cytokine produced mainly by activated
macrophages. It plays a crucial role in initiating and
amplifying the inflammatory response.
Interleukin-1 (IL-1): IL-1 is another pro-inflammatory
cytokine produced by macrophages and other immune
cells. It promotes the production of other cytokines,
activates endothelial cells, and enhances inflammation.
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Interleukin-6 (IL-6): IL-6 is produced by various cells,
including macrophages and T cells. It stimulates the acute
phase response, induces fever, and promotes the
production of other cytokines.
Interleukin-8 (IL-8): IL-8 is a chemokine that attracts and
activates neutrophils, a type of white blood cell involved in
the initial response to infection or tissue injury.
Interleukin-17 (IL-17): IL-17 is produced by a subset of T
cells known as Th17 cells. It induces the release of other
pro-inflammatory cytokines and chemokines, recruiting
immune cells to the site of inflammation.
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Interleukin-12 (IL-12): IL-12 is produced by antigen-
presenting cells, such as dendritic cells and macrophages.
It promotes the differentiation of T cells into a pro-
inflammatory subset known as Th1 cells.
Interleukin-23 (IL-23): IL-23 is closely related to IL-12 and
is involved in the activation and expansion of Th17 cells,
which contribute to chronic inflammation.
Inflammatory responses are complex and involve the
coordinated action of numerous cytokines and other
immune molecules.
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TNF-α: causing inflammation
Leukocyte recruitment: TNF-α promotes the recruitment of
immune cells, including neutrophils and monocytes, from
the bloodstream to the inflamed tissues. It induces
chemotaxis, which is the directed movement of immune
cells towards the site of inflammation.
Increased vascular permeability: TNF-α disrupts the
integrity of blood vessel walls by causing endothelial cells
to contract and form gaps between them. This increased
vascular permeability allows fluid, immune cells, and
inflammatory mediators to leak out of blood vessels and
enter the inflamed tissue, leading to swelling.
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Vascular changes
Endothelial cells respond to inflammatory mediators in
various ways;
• They increase expression of adhesion molecules on
their luminal surface.
• They assume more rounded appearance which creates
gaps between adjacent cells.
• They secrete cytokines which influence inflammatory
response.
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Histamine is the key mediator released from mast cells. It
causes vasodilation and increases capillary permeability
at the injured site allowing more blood to flow into the
area.
Plasma brings complement, antibodies, and other
protective molecules to the target site. The pain that
accompanies inflammation is due to pressure on the
sensory nerve endings by the swollen tissues, damage to
nerve endings by bacterial toxins, and bradykinin (A
vasoactive mediator released by the kinin system, an
enzyme system in the plasma which has a role in the
inflammatory response).
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Recruitment of phagocytic cells
Many mediators are chemoattractants. They recruit
phagocytic cells, predominantly neutrophils, to the infected
site where they phagocytose microbes and destroy them
intracellularly. Other cells namely,
monocytes/macrophages, small number of eosinophils
and basophils, and lymphocytes (at a late stage),
accumulate at sites of infection.
The migration of neutrophils and other leukocytes to
infected sites is dependent on adhesion molecules.
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Vasodialation
Vasodilation is the widening of
blood vessels as a result of the
relaxation of the blood vessel's
muscular walls. Vasodilation is a
mechanism to enhance blood
flow to areas of the body that are
lacking oxygen and/or nutrients.
MECHANISM OF INFLAMMATION
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Exudation-Edema
Exudate consists of fluid and
leukocytes that move to the site
of injury from the circulatory
system in response to local
inflammation. This inflammatory
response leads to blood vessel
dilatation and increased
permeability, resulting in
increased production of exudate.
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Emigration of cells
Transendothelial migration (TEM), the step in
inflammatory response in which leukocytes actually cross
the endothelial cells lining the blood vessels at the site of
inflammation, is a critical point in the regulation of this
response.
Chemotaxis
The chemotactic factor-mediated transmigration of leukocytes
after crossing several barriers to reach the interstitial tissues is
called chemotaxis. These chemoattractants act as immediate
mediators of inflammatory responses by regulating leukocyte
recruitment, infiltration, homing, and trafficking as well as their
development and function.
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ANTI-INFLAMMATORY CYTOKINES
Anti-inflammatory cytokines are a class of cytokines that play a
crucial role in regulating inflammation and dampening immune
responses. They work in opposition to pro-inflammatory cytokines
and help restore tissue homeostasis.
Interleukin-10 (IL-10): IL-10 is a potent anti-inflammatory cytokine
produced by various immune cells, including regulatory T cells,
macrophages, and dendritic cells. It inhibits the production of pro-
inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6, and
suppresses the activation of immune cells, such as T cells and
macrophages. IL-10 also promotes tissue repair and plays a role in
preventing excessive immune responses.
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Transforming growth factor-beta (TGF-beta): TGF-beta is a
versatile cytokine that has both pro-inflammatory and anti-
inflammatory properties, depending on the context. It acts as an
anti-inflammatory cytokine by inhibiting the production of pro-
inflammatory mediators, promoting the differentiation of regulatory T
cells, and suppressing the activation of immune cells. TGF-beta
also plays a crucial role in tissue repair and wound healing.
Interleukin-1 receptor antagonist (IL-1Ra): IL-1Ra is a naturally
occurring antagonist of interleukin-1 (IL-1), which is a pro-
inflammatory cytokine. IL-1Ra competes with IL-1 for binding to its
receptor, thereby preventing IL-1 signalling and dampening the
inflammatory response. It helps maintain a balance between pro-
inflammatory and anti-inflammatory signals.
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Interleukin-4 (IL-4): IL-4 is primarily known for its role in promoting
the differentiation of T cells into Th2 cells and stimulating antibody
production. However, IL-4 also exhibits anti-inflammatory properties
by inhibiting the production of pro-inflammatory cytokines and
promoting the activation of regulatory T cells. It is involved in
regulating allergic and asthmatic responses, where excessive
inflammation occurs.
Interleukin-37 (IL-37): IL-37 is a relatively newly discovered anti-
inflammatory cytokine that belongs to the IL-1 family. It is involved in
suppressing innate and adaptive immune responses by inhibiting the
production of pro-inflammatory cytokines and promoting the
expansion of regulatory T cells. IL-37 has been shown to have
therapeutic potential in various inflammatory disorders.
The interplay between proinflammatory and anti-inflammatory
cytokines is critical for a controlled and appropriately balanced