Inflammation (
Latin,
inflammatio, a setting on fire) is the complex biological
response of
vascular tissues to harmful
stimuli, such as
pathogens, damaged cells,
or irritants. Inflammation is a protective attempt by the organism
to remove the injurious stimuli as well as initiate the healing
process for the tissue. Inflammation is not a synonym for
infection. Even in cases where inflammation is
caused by infection, the two are not synonymous: infection is
caused by an exogenous pathogen, while inflammation is one of the
responses of the organism to the pathogen.
In the absence of inflammation, wounds and infections would never
heal and progressive destruction of the tissue would compromise the
survival of the organism. However, chronic inflammation can also
lead to a host of diseases, such as
hay
fever,
atherosclerosis, and
rheumatoid arthritis. It is for
that reason that inflammation is normally closely regulated by the
body.
Inflammation can be classified as either
acute or
chronic.
Acute inflammation is the initial
response of the body to harmful stimuli and is achieved by the
increased movement of
plasma and
leukocytes from the blood into the injured
tissues. A cascade of biochemical events propagates and matures the
inflammatory response, involving the local
vascular system, the
immune system, and various cells within the
injured tissue. Prolonged inflammation, known as
chronic
inflammation, leads to a progressive shift in the type of
cells which are present at the site of inflammation and is
characterized by simultaneous destruction and
healing of the tissue from the inflammatory
process.
Causes
Types
Comparison between acute and chronic
inflammation:
|
Acute |
Chronic |
Causative agent |
Pathogens, injured tissues |
Persistent acute inflammation due to non-degradable
pathogens, persistent foreign bodies, or autoimmune
reactions |
Major cells involved |
Neutrophils, mononuclear cells (monocytes,
macrophages) |
Mononuclear cells (monocytes, macrophages, lymphocytes,
plasma cells), fibroblasts |
Primary mediators |
Vasoactive amines, eicosanoids |
IFN-γ and other cytokines, growth factors, reactive
oxygen species, hydrolytic enzymes |
Onset |
Immediate |
Delayed |
Duration |
Few days |
Up to many months, or years |
Outcomes |
Resolution, abscess formation, chronic
inflammation |
Tissue destruction, fibrosis |
Clinical signs
The classic signs and symptoms of acute
inflammation:
English |
Latin |
Redness |
Rubor* |
Swelling |
Tumor/Turgor* |
Heat |
Calor* |
Pain |
Dolor* |
Loss of function |
Functio laesa** |
All the above signs may be
observed in specific instances, but no single sign must, as a
matter of course, be present.These are the original, so
called, "cardinal signs" of inflammation.*
Functio laesa is a bit of an apocryphal notion, as it is not really
unique to inflammation and is a characteristic of many disease
states.** |
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Infected ingrown toenail showing the
characteristic redness and swelling associated with acute
inflammation
Acute inflammation is a short-term process, usually appearing
within a few minutes or hours and ceasing upon the removal of the
injurious stimulus.. It is characterized by five cardinal signs:
- rubor (redness),
- calor (increased heat),
- tumor (swelling),
- dolor (pain), and
- functio laesa (loss of function).
The first four (classical signs) were described by
Celsus (ca 30 BC–38 AD), while
loss of function was added later by
Galen even though the attribution is disputed and the
origination of the fifth sign has also been ascribed to
Thomas Sydenham and
Virchow.
Redness and heat are due to increased blood flow at body core
temperature to the inflamed site; swelling is caused by
accumulation of fluid; pain is due to release of chemicals that
stimulate nerve endings. Loss of function has multiple
causes.
These five signs appear when acute inflammation occurs on the
body's surface, whereas acute inflammation of internal organs may
not result in the full set. Pain only happens where the appropriate
sensory nerve endings exist in the inflamed area — e.g., acute
inflammation of the lung (
pneumonia) does
not cause pain unless the inflammation involves the
parietal pleura, which does have
pain-sensitive nerve endings.
Process of acute inflammation
The process of acute inflammation is initiated by cells already
present in all tissues, mainly resident
macrophages,
dendritic cells, histiocytes, Kuppfer cells
and
mastocytes. At the onset of an
infection, burn, or other injuries, these cells undergo activation
and release inflammatory mediators responsible for the clinical
signs of inflammation. Vasodilation and its resulting increased
blood flow causes the redness (
rubor) and increased heat
(
calor). Increased permeability of the blood vessels
results in an exudation (leakage) of
plasma proteins and fluid into the tissue
(
oedema), which manifests itself as swelling
(
tumor). Some of the released mediators such as
bradykinin increase the sensitivity to pain
(
hyperalgesia,
dolor). The
mediator molecules also alter the blood vessels to permit the
migration of leukocytes, mainly
neutrophils, outside of the blood vessels
(extravasation) into the tissue. The neutrophils migrate along a
chemotactic gradient created by the
local cells to reach the site of injury. The loss of function
(
functio laesa) is probably the result of a neurological
reflex in response to pain.
In addition to cell-derived mediators, several acellular
biochemical cascade systems consisting of preformed plasma proteins
act in parallel to initiate and propagate the inflammatory
response. These include the
complement
system activated by bacteria, and the
coagulation and
fibrinolysis systems activated by
necrosis, e.g. a burn or a trauma.
The acute inflammatory response requires constant stimulation to be
sustained. Inflammatory mediators have short half lives and are
quickly degraded in the tissue. Hence, inflammation ceases once the
stimulus has been removed.
Exudative component
The
exudative component involves the movement of plasma
fluid, containing important
proteins such as
fibrin and
immunoglobulins (antibodies), into inflamed
tissue. This movement is achieved via the chemically induced
dilation and increased permeability of
blood vessels, which results in a net loss of
blood plasma. The increased collection
of fluid into the tissue causes it to swell (
edema).
Vascular changes
Acute inflammation is characterised by marked vascular changes,
including
vasodilation, increased
permeability, and the slowing of blood flow, which are induced by
the actions of various inflammatory mediators. Vasodilation occurs
first at the
arteriole level, progressing
to the
capillary level, and brings about a
net increase in the amount of blood present, causing the redness
and heat of inflammation. Increased permeability of the vessels
results in the movement of
plasma into
the tissues, with resultant
stasis due to the increase in
the concentration of the cells within blood - a condition
characterised by enlarged vessels packed with cells. Stasis allows
leukocytes to marginate (move) along the
endothelium, a process critical to their
recruitment into the tissues. Normal flowing blood prevents this,
as the
shearing force along the
periphery of the vessels moves cells in the blood into the middle
of the vessel.
Plasma cascade systems
- The complement system, when
activated, results in the increased removal of pathogens via
opsonisation and phagocytosis.
- The kinin system generates proteins
capable of sustaining vasodilation and other physical inflammatory
effects.
- The coagulation system or
clotting cascade which forms a protective protein mesh
over sites of injury.
- The fibrinolysis system,
which acts in opposition to the coagulation system, to
counterbalance clotting and generate several other inflammatory
mediators.
Plasma derived mediators
* non-exhaustive list
Name |
Produced by |
Description |
Bradykinin |
Kinin
system |
A vasoactive protein which is able to induce vasodilation,
increase vascular permeability, cause smooth muscle contraction,
and induce pain. |
C3 |
Complement
system |
Cleaves to produce C3a and C3b. C3a
stimulates histamine release by mast cells, thereby producing
vasodilation. C3b is able to bind to bacterial cell walls and act
as an opsonin, which marks the invader as a
target for phagocytosis. |
C5a |
Complement
system |
Stimulates histamine release by mast cells, thereby producing
vasodilation. It is also able to act as a chemoattractant to direct cells via
chemotaxis to the site of inflammation. |
Factor
XII (Hageman Factor) |
Liver |
A protein which circulates inactively, until activated by
collagen, platelets, or exposed basement membranes via conformational change. When activated,
it in turn is able to activate three plasma systems involved in
inflammation: the kinin system, fibrinolysis system, and
coagulation system. |
Membrane attack
complex |
Complement
system |
A complex of the complement proteins C5b,
C6, C7, C8, and
multiple units of C9. The
combination and activation of this range of complement proteins
forms the membrane attack complex, which is able to insert
into bacterial cell walls and causes cell lysis with ensuing
death. |
Plasmin |
Fibrinolysis
system |
Able to break down fibrin clots, cleave complement protein C3,
and activate Factor XII. |
Thrombin |
Coagulation
system |
Cleaves the soluble plasma protein fibrinogen to produce insoluble fibrin, which aggregates to form a blood clot. Thrombin can also bind to cells via
the PAR1 receptor to
trigger several other inflammatory responses, such as production of
chemokines and nitric oxide. |
Cellular component
The
cellular component involves
leukocytes, which normally reside in blood and
must move into the inflamed tissue via
extravasation to
aid in inflammation. Some act as
phagocytes, ingesting
bacteria, viruses, and cellular debris. Others
release enzymatic
granule
which damage pathogenic invaders. Leukocytes also release
inflammatory mediators which develop and maintain the inflammatory
response. Generally speaking, acute inflammation is mediated by
granulocytes, while chronic inflammation
is mediated by mononuclear cells such as
monocytes and
lymphocytes.
Leukocyte extravasation
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Neutrophils migrate from blood vessels
to the inflamed tissue via chemotaxis, where they remove pathogens
through phagocytosis and degranulation
Various
leukocytes are critically involved
in the initiation and maintenance of inflammation. These cells must
be able to get to the site of injury from their usual location in
the blood, therefore mechanisms exist to recruit and direct
leukocytes to the appropriate place. The process of leukocyte
movement from the blood to the tissues through the blood vessels is
known as
extravasation, and can be divided up into a
number of broad steps:
- Leukocyte localisation and recruitment to the
endothelium local to the site of inflammation – involving
margination and adhesion to the endothelial cells:
Recruitment of leukocytes is receptor-mediated. The products of
inflammation, such as histamine, promote
the immediate expression of P-selectin on
endothelial cell surfaces. This receptor binds weakly to
carbohydrate ligands on leukocyte surfaces and causes them to
"roll" along the endothelial surface as bonds are made and broken.
Cytokines from injured cells induce the expression of E-selectin on endothelial cells, which functions
similarly to P-selectin. Cytokines also induce the expression of
integrin ligands on endothelial cells,
which further slow leukocytes down. These weakly bound leukocytes
are free to detach if not activated by chemokines produced in
injured tissue. Activation increases the affinity of bound integrin
receptors for ligands on the endothelial cell surface, firmly
binding the leukocytes to the endothelium.
- Migration across the endothelium, known as
transmigration, via the process of diapedesis:
Chemokine gradients stimulate the adhered leukocytes to move
between endothelial cells and pass the basement membrane into the
tissues.
- Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the
tissue interstitium bind to extracellular matrix proteins via
expressed integrins and CD44 to prevent their
loss from the site. Chemoattractants
cause the leukocytes to move along a chemotactic gradient towards
the source of inflammation.
Cell derived mediators
* non-exhaustive list
Name |
Type |
Source |
Description |
Lysosome granules |
Enzymes |
Granulocytes |
These cells contain a large variety of enzymes which perform a
number of functions. Granules can be classified as either
specific or azurophilic depending upon the contents, and
are able to break down a number of substances, some of which may be
plasma-derived proteins which allow these enzymes to act as
inflammatory mediators. |
Histamine |
Vasoactive amine |
Mast cells, basophils, platelets |
Stored in preformed granules, histamine is released in response
to a number of stimuli. It causes arteriole dilation and increased venous permeability. |
IFN-γ |
Cytokine |
T-cells, NK cells |
Antiviral, immunoregulatory, and anti-tumour properties. This
interferon was originally called macrophage-activating factor, and
is especially important in the maintenance of chronic
inflammation. |
IL-8 |
Chemokine |
Primarily macrophages |
Activation and chemoattraction of neutrophils, with a weak
effect on monocytes and eosinophils. |
Leukotriene
B4 |
Eicosanoid |
Leukocytes |
Able to mediate leukocyte adhesion and activation, allowing
them to bind to the endothelium and migrate across it. In
neutrophils, it is also a potent chemoattractant, and is able to
induce the formation of reactive oxygen species and the release of
lysosome enzymes by these cells. |
Nitric
oxide |
Soluble gas |
Macrophages, endothelial cells, some
neurons |
Potent vasodilator, relaxes smooth muscle, reduces platelet
aggregation, aids in leukocyte recruitment, direct antimicrobial
activity in high concentrations. |
Prostaglandins |
Eicosanoid |
Mast cells |
A group of lipids which can cause vasodilation, fever, and
pain. |
TNF-α and IL-1 |
Cytokines |
Primarily macrophages |
Both affect a wide variety of cells to induce many similar
inflammatory reactions: fever, production of cytokines, endothelial
gene regulation, chemotaxis, leukocyte adherence, activation of
fibroblasts. Responsible for the systemic
effects of inflammation, such as loss of appetite and increased
heart rate. |
Morphologic patterns
Specific patterns of acute and chronic inflammation are seen during
particular situations that arise in the body, such as when
inflammation occurs on an
epithelial
surface, or
pyogenic bacteria are involved.
- Granulomatous inflammation: Characterised by
the formation of granulomas, they are the
result of a limited but diverse number of diseases, which include
among others tuberculosis, leprosy, and syphilis.
- Fibrinous inflammation: Inflammation resulting
in a large increase in vascular permeability allows fibrin to pass through the blood vessels. If an
appropriate procoagulative stimulus is present, such as
cancer cells, a fibrinous exudate is deposited. This is commonly
seen in serous cavities, where the
conversion of fibrinous exudate into a scar can occur between
serous membranes, limiting their function.
- Purulent inflammation: Inflammation resulting
in large amount of pus, which consists of
neutrophils, dead cells, and fluid. Infection by pyogenic bacteria
such as staphylococci is
characteristic of this kind of inflammation. Large, localised
collections of pus enclosed by surrounding tissues are called
abscesses.
- Serous inflammation: Characterised by the
copious effusion of non-viscous serous fluid, commonly produced by
mesothelial cells of serous membranes, but may be derived from
blood plasma. Skin blisters exemplify this
pattern of inflammation.
- Ulcerative inflammation: Inflammation
occurring near an epithelium can result in the necrotic loss of tissue from the surface, exposing
lower layers. The subsequent excavation in the epithelium is known
as an ulcer.
Inflammatory disorders
Abnormalities associated with inflammation comprise a large,
officially unrelated group of disorders which underlie a vast
variety of human diseases. The immune system is often involved with
inflammatory disorders, demonstrated in both
allergic reactions and some
myopathies, with many
immune system disorders resulting in
abnormal inflammation. Non-immune diseases with etiological origins
in inflammatory processes are thought to include cancer,
atherosclerosis, and
ischaemic heart disease.
A large variety of proteins are involved in inflammation, and any
one of them is open to a genetic mutation which impairs or
otherwise dysregulates the normal function and expression of that
protein.
Examples of disorders associated with inflammation include:
Allergies
An allergic reaction, formally known as
type 1 hypersensitivity, is the
result of an inappropriate immune response triggering inflammation.
A common example is
hay fever, which is
caused by a hypersensitive response by skin
mast cells to
allergens.
Pre-sensitised mast cells respond by
degranulating, releasing
vasoactive chemicals such as histamine. These
chemicals propagate an excessive inflammatory response
characterised by blood vessel dilation, production of
pro-inflammatory molecules, cytokine release, and recruitment of
leukocytes. Severe inflammatory response may mature into a systemic
response known as
anaphylaxis.
Other
hypersensitivity reactions
(
type 2 and
type 3) are mediated by antibody
reactions and induce inflammation by attracting leukocytes which
damage surrounding tissue.bjiun ijij
Myopathies
Inflammatory myopathies are caused by the immune system
inappropriately attacking components of muscle, leading to signs of
muscle inflammation. They may occur in conjunction with other
immune disorders, such as
systemic
sclerosis, and include
dermatomyositis,
polymyositis, and
inclusion body myositis.
Leukocyte defects
Due to the central role of leukocytes in the development and
propagation of inflammation, defects in leukocyte function often
result in a decreased capacity for inflammatory defense with
subsequent vulnerability to infection. Dysfunctional leukocytes may
be unable to correctly bind to blood vessels due to surface
receptor mutations, digest bacteria (
Chediak-Higashi syndrome), or
produce
microbicides (
chronic granulomatous
disease). Additionally, diseases affecting the
bone marrow may result in abnormal or few
leukocytes.
Pharmacological
Certain drugs or exogenic chemical compounds are known to affect
inflammation.
Vitamin A deficiency causes
an increase in inflammatory responses, and
anti-inflammatory drugs work specifically
by inhibiting normal inflammatory components.
Cancer
Inflammation orchestrates the microenvironment around tumours,
contributing to proliferation, survival and migration. Cancer cells
use
selectins,
chemokines and their receptors for invasion,
migration and metastasis. On the other hand, many cells of the
immune system contribute to
cancer
immunology, suppressing cancer.
Termination
The inflammatory response must be actively terminated when no
longer needed to prevent unnecessary "bystander" damage to tissues.
Failure to do so results in chronic inflammation, cellular
destruction, and attempts to heal the inflamed tissue. One
intrinsic mechanism employed to terminate inflammation is the short
half-life of inflammatory mediators
in vivo. They have a
limited time frame to affect their target before breaking down into
non-functional components, therefore constant inflammatory
stimulation is needed to propagate their effects.
Active mechanisms which serve to terminate inflammation include:
Systemic effects
An
infectious organism can
escape the confines of the immediate tissue via the
circulatory system or
lymphatic system, where it may spread to
other parts of the body. If an organism is not contained by the
actions of acute inflammation it may gain access to the lymphatic
system via nearby
lymph vessels. An
infection of the lymph vessels is known as
lymphangitis, and infection of a lymph node is
known as
lymphadenitis. A pathogen can
gain access to the bloodstream through lymphatic drainage into the
circulatory system.
When inflammation overwhelms the host,
systemic inflammatory
response syndrome is diagnosed. When it is due to
infection, the term
sepsis
is applied, with
bacteremia being applied
specifically for bacterial sepsis and
viremia specifically to viral sepsis.
Vasodilation and organ dysfunction are serious
problems associated with widespread infection that may lead to
septic shock and death.
Acute-phase proteins
Inflammation also induces high systemic levels of
acute-phase proteins. In acute
inflammation, these proteins prove beneficial, however in chronic
inflammation they can contribute to
amyloidosis. These proteins include
C-reactive protein,
serum amyloid A, and
serum amyloid P,
vasopressin, which cause a range of systemic
effects including:
Leukocyte numbers
Inflammation often affects the numbers of leukocytes present in the
body:
- Leukocytosis is often seen during
inflammation induced by infection, where it results in a large
increase in the amount of leukocytes in the blood, especially
immature cells. Leukocyte numbers usually increase to between 15
000 and 20 000 cells per ml, but extreme cases
can see it approach 100 000 cells per ml. Bacterial infection
usually results in an increase of neutrophils, creating neutrophilia, whereas diseases such as asthma, hay fever, and
parasite infestation result in an increase in eosinophils, creating eosinophilia.
- Leukopenia can be induced by certain
infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis,
and some cancers.
Systemic inflammation and obesity
With the discovery of
interleukins (IL),
the concept of
systemic inflammation developed. Although
the processes involved are identical to tissue inflammation,
systemic inflammation is not confined to a particular tissue but
involves the
endothelium and other organ
systems.
High levels of several inflammation-related markers such as
IL-6,
IL-8, and
TNF-α are associated with
obesity. During clinical studies,
inflammatory-related molecule levels were reduced and increased
levels of anti-inflammatory molecules were seen within four weeks
after patients began a very low calorie diet. The association of
systemic inflammation with
insulin
resistance and
atherosclerosis
is the subject of intenseresearch.
Outcomes
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Scars present on the skin, evidence of
fibrosis and healing of a wound
The outcome in a particular circumstance will be determined by the
tissue in which the injury has occurred and the injurious agent
that is causing it. Here are the possible outcomes to
inflammation:
- Resolution
The complete restoration of the inflamed tissue back to a normal
status.
Inflammatory measures such as vasodilation, chemical production,
and leukocyte infiltration cease, and damaged parenchymal cells regenerate.
In situations where limited or short lived inflammation has
occurred this is usually the outcome.
- Fibrosis
Large amounts of tissue destruction, or damage in tissues unable to
regenerate, can not be regenerated completely by the body.
Fibrous scarring occurs in these areas of
damage, forming a scar composed primarily of collagen.
The scar will not contain any specialized structures, such as
parenchymal cells, hence functional
impairment may occur.
- Abscess Formation
A cavity is formed containing pus, an opaque liquid containing dead
white blood cells and bacteria with general debris from destroyed
cells.
- Chronic inflammation
In acute inflammation, if the injurious agent persists then chronic
inflammation will ensue.
This process, marked by inflammation lasting many days, months or
even years, may lead to the formation of a chronic wound.
Chronic inflammation is characterised by the dominating presence of
macrophages in the injured tissue.
These cells are powerful defensive agents of the body, but the
toxins they release (including reactive oxygen species) are
injurious to the organism's own tissues as well as invading
agents.
Consequently, chronic inflammation is almost always accompanied by
tissue destruction.
Examples
Inflammation is usually indicated by adding the suffix "
-itis", as shown below. However, some conditions
such as
asthma and
pneumonia do not follow this convention. More
examples are available at
list of types of
inflammation.
Image:Acute_Appendicitis.jpg|Acute appendicitis
Image:Dermatitis.jpg|Acute dermatitis
Image:Streptococcus pneumoniae meningitis, gross pathology 33 lores.jpg|Acute infective meningitis
Image:Tonsillitis.jpg|Acute tonsillitis
See also
References
- Stedman's Medical Dictionary, Twenty-fifth Edition, Williams
& Wilkins, 1990.
- Disturbance of function (functio laesa): the legendary fifth
cardinal sign of inflammation, added by Galen to the four cardinal
signs of Celsus. Bull N Y Acad Med. 1971 March; 47(3): 303–322
Further reading
Kyriakis JM, Avruch J. Sounding the alarm: protein kinase cascades
activated by stress and inflammation. J Biol Chem. 1996 Oct
4;271(40):24313-6. Review. PMID: 8798679
Salminen A, Kauppinen A, Suuronen T, Kaarniranta K. SIRT1 longevity
factor suppresses NF-kappaB -driven immune responses: regulation of
aging via NF-kappaB acetylation? Bioessays. 2008
Oct;30(10):939-42.
Rangan G, Wang Y, Harris D. NF-kappaB signalling in chronic kidney
disease. Front Biosci. 2009 Jan 1;14:3496-522. Review. PMID:
19273289
External links