Inflammation (from la,
inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a g ...
s, damaged cells, or
irritants,
and is a protective response involving
immune cells
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mul ...
,
blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out
necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.
The five
cardinal signs are heat, pain, redness, swelling, and
loss of function (Latin ''calor'', ''dolor'', ''rubor'', ''tumor'', and ''functio laesa''). Inflammation is a generic response, and therefore it is considered as a mechanism of
innate immunity, as compared to
adaptive immunity
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
, which is specific for each pathogen.
Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. In contrast, too much inflammation, in the form of chronic inflammation, is associated with various diseases, such as
hay fever,
periodontal disease,
atherosclerosis, and
osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the ...
.
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 (in particular
granulocytes) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local
vascular system, the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
, and various cells within the injured tissue. Prolonged inflammation, known as ''chronic inflammation'', leads to a progressive shift in the type of cells present at the site of inflammation, such as
mononuclear cells, and is characterized by simultaneous destruction and
healing
With physical trauma or disease suffered by an organism, healing involves the repairing of damaged tissue(s), organs and the biological system as a whole and resumption of (normal) functioning. Medicine includes the process by which the cells ...
of the tissue from the inflammatory process.
Inflammation has also been classified as Type 1 and Type 2 based on the type of
cytokines and
helper T cells
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
(Th1 and Th2) involved.
Inflammation is not a synonym for
infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
. Infection describes the interaction between the action of microbial invasion and the reaction of the body's inflammatory response—the two components are considered together when discussing an infection, and the word is used to imply a microbial invasive cause for the observed inflammatory reaction. Inflammation, on the other hand, describes purely the body's immunovascular response—whatever the cause may be. But because of how often the two are
correlated
In statistics, correlation or dependence is any statistical relationship, whether causal or not, between two random variables or bivariate data. Although in the broadest sense, "correlation" may indicate any type of association, in statistic ...
, words ending in the suffix ''
-itis
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
'' (which refers to inflammation) are sometimes informally described as referring to infection. For example, the word ''
urethritis'' strictly means only "urethral inflammation", but clinical
health care providers usually discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis.
However, the inflammation–infection distinction becomes crucial for situations in
pathology
Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...
and
medical diagnosis
Medical diagnosis (abbreviated Dx, Dx, or Ds) is the process of determining which disease or condition explains a person's symptoms and signs. It is most often referred to as diagnosis with the medical context being implicit. The information r ...
where inflammation is not driven by microbial invasion, such as the cases of
atherosclerosis,
trauma
Trauma most often refers to:
*Major trauma, in physical medicine, severe physical injury caused by an external source
*Psychological trauma, a type of damage to the psyche that occurs as a result of a severely distressing event
*Traumatic inju ...
,
ischemia, and
autoimmune diseases (including
type III hypersensitivity
Type III hypersensitivity, in the Gell and Coombs classification of allergic reactions, occurs when there is accumulation of immune complexes (antigen-antibody complexes) that have not been adequately cleared by innate immune cells, giving rise ...
).
Causes
Types
*
Appendicitis
Appendicitis is inflammation of the appendix. Symptoms commonly include right lower abdominal pain, nausea, vomiting, and decreased appetite. However, approximately 40% of people do not have these typical symptoms. Severe complications of a r ...
*
Bursitis
*
Colitis
*
Cystitis
*
Dermatitis
Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved c ...
*
Epididymitis
*
Encephalitis
*
Gingivitis
Gingivitis is a non-destructive disease that causes inflammation of the gums. The most common form of gingivitis, and the most common form of periodontal disease overall, is in response to bacterial biofilms (also called plaque) that is attac ...
*
Meningitis
*
Myelitis
*
Nephritis
*
Neuritis
Neuritis () is inflammation of a nerve or the general inflammation of the peripheral nervous system. Inflammation, and frequently concomitant demyelination, cause impaired transmission of neural signals and leads to aberrant nerve function. Neu ...
*
Pancreatitis
Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic p ...
*
Periodontitis
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main cau ...
*
Pharyngitis
Pharyngitis is inflammation of the back of the throat, known as the pharynx. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, difficulty swallowing, swollen lymph nodes, and a hoa ...
*
Phlebitis
*
Prostatitis
*
RSD/CRPS
*
Rhinitis
*
Sinusitis
*
Tendonitis
*
Tonsillitis
Tonsillitis is inflammation of the tonsils in the upper part of the throat. It can be acute or chronic. Acute tonsillitis typically has a rapid onset. Symptoms may include sore throat, fever, enlargement of the tonsils, trouble swallowing, a ...
*
Urethritis
*
Vasculitis
*
Vaginitis
Vaginitis, also known as vulvovaginitis, is inflammation of the vagina and vulva. Symptoms may include itching, burning, pain, discharge, and a bad smell. Certain types of vaginitis may result in complications during pregnancy.
The three ma ...
Acute
Acute inflammation occurs immediately upon injury, lasting only a few days.
Cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s and
chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...
s promote the migration of
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s and
macrophages to the site of inflammation.
Pathogens, allergens, toxins, burns, and frostbite are some of the typical causes of acute inflammation.
Toll-like receptors (TLRs) recognize microbial pathogens.
Acute inflammation can be a defensive mechanism to protect tissues against injury.
Inflammation lasting 2–6 weeks is designated subacute inflammation.
Cardinal signs
Acute inflammation is a short-term process, usually appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus.
It involves a coordinated and systemic mobilization response locally of various immune, endocrine and neurological mediators of acute inflammation. In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and then ceases. It is characterized by five
cardinal signs:
The traditional names for signs of inflammation come from Latin:
*
Dolor (
pain)
* Calor (
heat
In thermodynamics, heat is defined as the form of energy crossing the boundary of a thermodynamic system by virtue of a temperature difference across the boundary. A thermodynamic system does not ''contain'' heat. Nevertheless, the term is ...
)
*
Rubor (redness)
* Tumor (
swelling)
*
Functio laesa
Functio laesa is a term used in medicine to refer to a loss of function or a disturbance of function.
It was identified as the fifth sign of acute inflammation by Galen, who added it to the four signs identified by Celsus (''tumor'', ''rubor'', '' ...
(loss of function)
The first four (classical signs) were described by
Celsus (–38 AD), while ''loss of function'' was probably added later by
Galen
Aelius Galenus or Claudius Galenus ( el, Κλαύδιος Γαληνός; September 129 – c. AD 216), often Anglicized as Galen () or Galen of Pergamon, was a Greek physician, surgeon and philosopher in the Roman Empire. Considered to be o ...
.
However, the addition of this fifth sign has also been ascribed to
Thomas Sydenham and
Virchow
Rudolf Ludwig Carl Virchow (; or ; 13 October 18215 September 1902) was a German physician, anthropologist, pathologist, prehistorian, biologist, writer, editor, and politician. He is known as "the father of modern pathology" and as the founder ...
.
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 the release of chemicals such as bradykinin and histamine that stimulate nerve endings. Loss of function has multiple causes.
Acute inflammation of the lung (usually as in response to
pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
) does not cause pain unless the inflammation involves the
parietal pleura, which does have
pain-sensitive nerve endings.
Acute process
The process of acute inflammation is initiated by resident immune cells already present in the involved tissue, mainly resident
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
,
dendritic cells,
histiocytes
A histiocyte is a vertebrate cell that is part of the mononuclear phagocyte system (also known as the reticuloendothelial system or lymphoreticular system). The mononuclear phagocytic system is part of the organism's immune system. The histioc ...
,
Kupffer cells
Kupffer cells, also known as stellate macrophages and Kupffer–Browicz cells, are specialized cells localized in the liver within the lumen of the liver sinusoids and are adhesive to their endothelial cells which make up the blood vessel walls. K ...
and
mast cells. These cells possess surface receptors known as ''
pattern recognition receptor
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
s'' (PRRs), which recognize (i.e., bind) two subclasses of molecules:
pathogen-associated molecular patterns (PAMPs) and
damage-associated molecular pattern
Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger-associated ...
s (DAMPs). PAMPs are compounds that are associated with various
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a g ...
s, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related injury and cell damage.
At the onset of an infection, burn, or other injuries, these cells undergo activation (one of the PRRs recognize a PAMP or DAMP) 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 (
edema), which manifests itself as swelling (''tumor''). Some of the released mediators such as
bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor an ...
increase the sensitivity to pain (
hyperalgesia, ''dolor''). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly
neutrophils and
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
, to flow out of the blood vessels (extravasation) and 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
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism ...
and
fibrinolysis systems activated by
necrosis (e.g., burn, trauma).
Acute inflammation may be regarded as the first line of defense against injury. Acute inflammatory response requires constant stimulation to be sustained. Inflammatory mediators are short-lived and are quickly degraded in the tissue. Hence, acute inflammation begins to cease once the stimulus has been removed.
Chronic
Chronic inflammation is inflammation that lasts for months or years.
Macrophages,
lymphocytes, and
plasma cells predominate in chronic inflammation, in contrast to the neutrophils that predominate in acute inflammation.
Diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
,
cardiovascular disease,
allergies, and
chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
(COPD) are examples of diseases mediated by chronic inflammation.
Obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
, smoking, stress and insufficient diet are some of the factors that promote chronic inflammation.
A 2014 study reported that 60% of Americans had at least one chronic inflammatory condition, and 42% had more than one.
Cardinal signs
Common signs and symptoms that develop during chronic inflammation are:
* Body pain, arthralgia, myalgia
* Chronic fatigue and insomnia
* Depression, anxiety and mood disorders
* Gastrointestinal complications such as constipation, diarrhea, and acid reflux
* Weight gain or loss
* Frequent infections
Vascular component
Vasodilation and increased permeability
As defined, acute inflammation is an immunovascular response to inflammatory stimuli. This means acute inflammation can be broadly divided into a vascular phase that occurs first, followed by a cellular phase involving immune cells (more specifically myeloid
granulocytes in the acute setting). The vascular component of acute inflammation involves the movement of
plasma fluid, containing important
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s such as
fibrin and
immunoglobulins (
antibodies), into inflamed tissue.
Upon contact with PAMPs, tissue
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
and
mastocytes release vasoactive amines such as
histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discover ...
and
serotonin, as well as
eicosanoids such as
prostaglandin E2 and
leukotriene B4 to remodel the local vasculature. Macrophages and endothelial cells release
nitric oxide. These mediators vasodilate and permeabilize the
blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide awa ...
s, which results in the net distribution of
blood plasma
Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the int ...
from the vessel into the tissue space. The increased collection of fluid into the tissue causes it to swell (
edema). This exuded tissue fluid contains various antimicrobial mediators from the plasma such as
complement,
lysozyme,
antibodies, which can immediately deal damage to microbes, and opsonise the microbes in preparation for the cellular phase. If the inflammatory stimulus is a lacerating wound, exuded
platelets,
coagulants,
plasmin and
kinins can
clot the wounded area and provide
haemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, whi ...
in the first instance. These clotting mediators also provide a structural staging framework at the inflammatory tissue site in the form of a
fibrin lattice – as would construction
scaffolding at a construction site – for the purpose of aiding phagocytic debridement and
wound repair later on. Some of the exuded tissue fluid is also funneled by
lymphatics to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the
adaptive immune system
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
.
Acute inflammation is characterized by marked vascular changes, including
vasodilation, increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the
arteriole level, progressing to the
capillary
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the bod ...
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
Stasis (from Greek στάσις "a standing still") may refer to:
* A state in stability theory, in which all forces are equal and opposing, therefore they cancel out each other
* Stasis (political history), a period of civil war within an ancient ...
due to the increase in the concentration of the cells within blood – a condition characterized by enlarged vessels packed with cells. Stasis allows
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mu ...
to marginate (move) along the
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
, 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, creates a cascade of chemical reactions that promotes
opsonization
Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed (i.e. ...
,
chemotaxis, and
agglutination
In linguistics, agglutination is a morphological process in which words are formed by stringing together morphemes, each of which corresponds to a single syntactic feature. Languages that use agglutination widely are called agglutinative la ...
, and produces the
MAC.
* 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
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
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
, viruses, and cellular debris. Others release enzymatic
granules that damage pathogenic invaders. Leukocytes also release inflammatory mediators that develop and maintain the inflammatory response. In general, acute inflammation is mediated by
granulocytes, whereas chronic inflammation is mediated by mononuclear cells such as
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s and
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic a ...
s.
Leukocyte extravasation
Various
leukocytes, particularly neutrophils, are critically involved in the initiation and maintenance of inflammation. These cells must be able to move 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 broadly divided up into a number of steps:
# Leukocyte margination and endothelial adhesion: The white blood cells within the vessels which are generally centrally located move peripherally towards the walls of the vessels.
Activated macrophages in the tissue release
cytokines such as
IL-1 and
TNFα
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, which in turn leads to production of
chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...
s that bind to
proteoglycans forming gradient in the inflamed tissue and along the
endothelial
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
wall. Inflammatory cytokines induce the immediate expression of
P-selectin on endothelial cell surfaces and P-selectin binds weakly to carbohydrate ligands on the surface of leukocytes and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines released 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
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...
ligands such as
ICAM-1 and
VCAM-1 on endothelial cells, which mediate the adhesion and further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue after
signal transduction via respective
G protein-coupled receptors that activates integrins on the leukocyte surface for firm adhesion. Such activation increases the affinity of bound integrin receptors for ICAM-1 and VCAM-1 on the endothelial cell surface, firmly binding the leukocytes to the endothelium.
# Migration across the endothelium, known as'' transmigration, ''via the process of
diapedesis
Leukocyte extravasation (also commonly known as leukocyte adhesion cascade or diapedesis – the passage of cells through the intact vessel wall) is the movement of leukocytes out of the circulatory system and towards the site of tissue damage ...
: Chemokine gradients stimulate the adhered leukocytes to move between adjacent endothelial cells. The endothelial cells retract and the leukocytes pass through the basement membrane into the surrounding tissue using adhesion molecules such as ICAM-1.
# Movement of leukocytes within the tissue via
chemotaxis: Leukocytes reaching the tissue interstitium bind to
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
proteins via expressed integrins and
CD44 to prevent them from leaving the site. A variety of molecules behave as
chemoattractant
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
s, for example, C3a or C5, and cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.
Phagocytosis
Extravasated neutrophils in the cellular phase come into contact with microbes at the inflamed tissue.
Phagocytes express cell-surface endocytic
pattern recognition receptors
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells o ...
(PRRs) that have affinity and efficacy against non-specific
microbe-associated molecular patterns (PAMPs). Most PAMPs that bind to endocytic PRRs and initiate
phagocytosis are cell wall components, including complex carbohydrates such as
mannans
Mannans are polymers containing the sugar mannose as a principal component.
They are a type of polysaccharide comprise hemicellulose, a major source of biomass found in higher plants such as softwoods. These polymers also typically contain two ot ...
and β-
glucans,
lipopolysaccharides (LPS),
peptidoglycans, and surface proteins. Endocytic PRRs on phagocytes reflect these molecular patterns, with
C-type lectin receptors binding to mannans and β-glucans, and
scavenger receptors binding to LPS.
Upon endocytic PRR binding,
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
-
myosin cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...
rearrangement adjacent to the plasma membrane occurs in a way that endocytoses the plasma membrane containing the PRR-PAMP complex, and the microbe.
Phosphatidylinositol
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
and
Vps34-
Vps15-
Beclin1 signalling pathways have been implicated to traffic the endocytosed phagosome to intracellular
lysosomes, where fusion of the phagosome and the lysosome produces a phagolysosome. The
reactive oxygen species,
superoxides
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of th ...
and
hypochlorite bleach within the phagolysosomes then kill microbes inside the phagocyte.
Phagocytic efficacy can be enhanced by
opsonization
Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed (i.e. ...
. Plasma derived complement
C3b
C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptot ...
and antibodies that exude into the inflamed tissue during the vascular phase bind to and coat the microbial antigens. As well as endocytic PRRs, phagocytes also express
opsonin receptors
Fc receptor and
complement receptor 1 (CR1), which bind to antibodies and C3b, respectively. The co-stimulation of endocytic PRR and opsonin receptor increases the efficacy of the phagocytic process, enhancing the
lysosomal elimination of the infective agent.
Cell-derived mediators
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
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
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
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, ...
,
leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria '' Mycobacterium leprae'' or '' Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve d ...
,
sarcoidosis
Sarcoidosis (also known as ''Besnier-Boeck-Schaumann disease'') is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly af ...
, and
syphilis
Syphilis () is a sexually transmitted infection caused by the bacterium '' Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms of syphilis vary depending in which of the four stages it presents (primary, secondary, latent, a ...
.
* 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. The deposit sometimes forms a pseudomembrane sheet. During inflammation of the intestine (
pseudomembranous colitis
Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.
In a medical context, the label ''colitis'' (without qualificatio ...
), pseudomembranous tubes can be formed.
* 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
The mesothelium is a membrane composed of simple squamous epithelial cells of mesodermal origin, which forms the lining of several body cavities: the pleura ( pleural cavity around the lungs), peritoneum ( abdominopelvic cavity including the ...
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.
Disorders
Inflammatory abnormalities are a large group of disorders that underlie a vast variety of human diseases. The immune system is often involved with inflammatory disorders, as demonstrated in both
allergic reaction
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...
s and some
myopathies, with many
immune system disorder
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s resulting in abnormal inflammation. Non-immune diseases with causal origins in inflammatory processes include cancer,
atherosclerosis, and
ischemic heart disease.
Examples of disorders associated with inflammation include:
*
Acne vulgaris
*
Asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
*
Autoimmune diseases
*
Autoinflammatory disease
Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of ...
s
*
Celiac disease
*
Chronic prostatitis
*
Colitis
*
Diverticulitis
*
Familial Mediterranean Fever
*
Glomerulonephritis
*
Hidradenitis suppurativa
Hidradenitis suppurativa (HS), sometimes known as acne inversa or Verneuil's disease, is a long-term dermatological condition characterized by the occurrence of inflamed and swollen lumps. These are typically painful and break open, releasin ...
*
Hypersensitivities
*
Inflammatory bowel diseases
*
Interstitial cystitis
*
Lichen planus
*
Mast Cell Activation Syndrome
*
Mastocytosis
*
Otitis
*
Pelvic inflammatory disease
*
Peripheral ulcerative keratitis
*
Pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
*
Reperfusion injury
*
Rheumatic fever
*
Rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are inv ...
*
Rhinitis
*
Sarcoidosis
Sarcoidosis (also known as ''Besnier-Boeck-Schaumann disease'') is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly af ...
*
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient ...
*
Vasculitis
Atherosclerosis
Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of atherosclerosis from initiation through progression and, ultimately, the thrombotic complications from it. These new findings provide important links between risk factors and the mechanisms of
atherogenesis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no ...
. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker
C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, the anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights on inflammation contribute to the etiology of atherosclerosis, and the practical clinical applications in risk stratification and the targeting of therapy for atherosclerosis.
Allergy
An allergic reaction, formally known as
type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation, vasodilation, and nerve irritation. A common example is
hay fever, which is caused by a hypersensitive response by
mast cells to
allergen
An allergen is a type of antigen that produces an abnormally vigorous immune response in which the immune system fights off a perceived threat that would otherwise be harmless to the body. Such reactions are called allergies.
In technical t ...
s. Pre-sensitised mast cells respond by
degranulating, releasing
vasoactive
A vasoactive substance is an endogenous agent or pharmaceutical drug that has the effect of either increasing or decreasing blood pressure and/or heart rate through its vasoactivity, that is, vascular activity (effect on blood vessels). By a ...
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
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follo ...
.
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
Dermatomyositis (DM) is a long-term inflammatory disorder which affects skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over time. These may occur suddenly or develop over months. Other symptoms may inc ...
,
polymyositis
Polymyositis (PM) is a type of chronic inflammation of the muscles (inflammatory myopathy) related to dermatomyositis and inclusion body myositis. Its name means "inflammation of many muscles" ('' poly-'' + '' myos-'' + '' -itis''). The inflam ...
, and
inclusion body myositis.
Leukocyte defects
Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte functionality 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 (
Chédiak–Higashi syndrome), or produce
microbicide
An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ...
s (
chronic granulomatous disease). In addition, diseases affecting the
bone marrow may result in abnormal or few leukocytes.
Pharmacological
Certain drugs or exogenous chemical compounds are known to affect inflammation.
Vitamin A deficiency, for example, causes an increase in inflammatory responses, and
anti-inflammatory drugs work specifically by inhibiting the enzymes that produce inflammatory
eicosanoids. Additionally, certain illicit drugs such as
cocaine
Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...
and
ecstasy may exert some of their detrimental effects by activating transcription factors intimately involved with inflammation (e.g.
NF-κB).
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.
Molecular intersection between receptors of steroid hormones, which have important effects on cellular development, and transcription factors that play key roles in inflammation, such as
NF-κB, may mediate some of the most critical effects of inflammatory stimuli on cancer cells.
This capacity of a mediator of inflammation to influence the effects of steroid hormones in cells is very likely to affect carcinogenesis. On the other hand, due to the modular nature of many steroid hormone receptors, this interaction may offer ways to interfere with cancer progression, through targeting of a specific protein domain in a specific cell type. Such an approach may limit side effects that are unrelated to the tumor of interest, and may help preserve vital homeostatic functions and developmental processes in the organism.
According to a review of 2009, recent data suggests that cancer-related inflammation (CRI) may lead to accumulation of random genetic alterations in cancer cells.
Role in cancer
In 1863,
Rudolf Virchow hypothesized that the origin of cancer was at sites of chronic inflammation.
At present, chronic inflammation is estimated to contribute to approximately 15% to 25% of human cancers.
Mediators and DNA damage in cancer
An inflammatory mediator is a messenger that acts on blood vessels and/or cells to promote an inflammatory response.
Inflammatory mediators that contribute to neoplasia include
prostaglandins, inflammatory
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s such as
IL-1β
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin ...
,
TNF-α,
IL-6 and
IL-15 and
chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...
s such as
IL-8 and
GRO-alpha.
These inflammatory mediators, and others, orchestrate an environment that fosters proliferation and survival.
Inflammation also causes DNA damages due to the induction of
reactive oxygen species (ROS) by various intracellular inflammatory mediators.
In addition,
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mu ...
and other
phagocytic cells attracted to the site of inflammation induce DNA damages in proliferating cells through their generation of ROS and
reactive nitrogen species (RNS). ROS and RNS are normally produced by these cells to fight infection.
ROS, alone, cause more than 20 types of DNA damage.
Oxidative DNA damages cause both
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s
and epigenetic alterations.
RNS also cause mutagenic DNA damages.
A normal cell may undergo
carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
to become a cancer cell if it is frequently subjected to DNA damage during long periods of chronic inflammation. DNA damages may cause genetic
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s due to
inaccurate repair. In addition, mistakes in the DNA repair process may cause
epigenetic alterations.
Mutations and epigenetic alterations that are replicated and provide a selective advantage during somatic cell proliferation may be carcinogenic.
Genome-wide analyses of human cancer tissues reveal that a single typical cancer cell may possess roughly 100 mutations in
coding regions, 10-20 of which are
"driver mutations" that contribute to cancer development.
However, chronic inflammation also causes epigenetic changes such as
DNA methylations, that are often more common than mutations. Typically, several hundreds to thousands of genes are methylated in a cancer cell (see
DNA methylation in cancer DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the prom ...
). Sites of oxidative damage in
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...
can recruit complexes that contain
DNA methyltransferases (DNMTs), a histone deacetylase (
SIRT1), and a
histone methyltransferase (EZH2), and thus induce DNA methylation.
DNA methylation of a
CpG island
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG i ...
in a
promoter region
In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein ( mRNA), or can have a function in and ...
may cause silencing of its downstream gene (see
CpG site and
regulation of transcription in cancer). DNA repair genes, in particular, are frequently inactivated by methylation in various cancers (see
hypermethylation of DNA repair genes in cancer). A 2018 report
evaluated the relative importance of mutations and epigenetic alterations in progression to two different types of cancer. This report showed that epigenetic alterations were much more important than mutations in generating gastric cancers (associated with inflammation).
However, mutations and epigenetic alterations were of roughly equal importance in generating esophageal squamous cell cancers (associated with
tobacco chemicals and
acetaldehyde, a product of alcohol metabolism).
HIV and AIDS
It has long been recognized that infection with HIV is characterized not only by development of profound
immunodeficiency but also by sustained inflammation and immune activation.
A substantial body of evidence implicates chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency.
Many now regard HIV infection not only as an evolving virus-induced immunodeficiency, but also as chronic inflammatory disease. Even after the introduction of
effective antiretroviral therapy (ART) and effective suppression of viremia in HIV-infected individuals, chronic inflammation persists. Animal studies also support the relationship between immune activation and progressive cellular immune deficiency:
SIVsm infection of its natural nonhuman primate hosts, the
sooty mangabey, causes high-level viral replication but limited evidence of disease. This lack of pathogenicity is accompanied by a lack of inflammation, immune activation and cellular proliferation. In sharp contrast, experimental
SIVsm infection of
rhesus macaque produces immune activation and AIDS-like disease with many parallels to human HIV infection.
Delineating how
CD4
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ce ...
T cells are depleted and how chronic inflammation and immune activation are induced lies at the heart of understanding HIV pathogenesis––one of the top priorities for HIV research by the Office of AIDS Research,
National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the lat ...
. Recent studies demonstrated that
caspase-1
Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...
-mediated
pyroptosis Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of va ...
, a highly inflammatory form of programmed cell death, drives CD4 T-cell depletion and inflammation by HIV.
These are the two signature events that propel HIV disease progression to
AIDS. Pyroptosis appears to create a pathogenic vicious cycle in which dying CD4 T cells and other immune cells (including macrophages and neutrophils) release inflammatory signals that recruit more cells into the infected lymphoid tissues to die. The feed-forward nature of this inflammatory response produces chronic inflammation and tissue injury. Identifying pyroptosis as the predominant mechanism that causes CD4 T-cell depletion and chronic inflammation, provides novel therapeutic opportunities, namely caspase-1 which controls the pyroptotic pathway. In this regard, pyroptosis of CD4 T cells and secretion of pro-inflammatory cytokines such as
IL-1β
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin ...
and
IL-18 can be blocked in HIV-infected human lymphoid tissues by addition of the caspase-1 inhibitor VX-765,
which has already proven to be safe and well tolerated in phase II human clinical trials. These findings could propel development of an entirely new class of "anti-AIDS" therapies that act by targeting the host rather than the virus. Such agents would almost certainly be used in combination with ART. By promoting "tolerance" of the virus instead of suppressing its replication, VX-765 or related drugs may mimic the evolutionary solutions occurring in multiple monkey hosts (e.g. the sooty mangabey) infected with species-specific lentiviruses that have led to a lack of disease, no decline in CD4 T-cell counts, and no chronic inflammation.
Resolution
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, and cellular destruction. Resolution of inflammation occurs by different mechanisms in different tissues.
Mechanisms that serve to terminate inflammation include:
Connection to depression
There is evidence for a link between inflammation and
depression. Inflammatory processes can be triggered by negative cognitions or their consequences, such as stress, violence, or deprivation. Thus, negative cognitions can cause inflammation that can, in turn, lead to depression.
In addition, there is increasing evidence that inflammation can cause depression because of the increase of cytokines, setting the brain into a "sickness mode". Classical symptoms of being physically sick, such as lethargy, show a large overlap in behaviors that characterize depression. Levels of cytokines tend to increase sharply during the depressive episodes of people with bipolar disorder and drop off during remission. Furthermore, it has been shown in clinical trials that anti-inflammatory medicines taken in addition to antidepressants not only significantly improves symptoms but also increases the proportion of subjects positively responding to treatment.
Inflammations that lead to serious depression could be caused by common infections such as those caused by a virus, bacteria or even parasites.
Connection to delirium
There is evidence for a link between inflammation and
delirium based on the results of a recent longitudinal study investigating CRP in COVID-19 patients.
Systemic effects
An
infectious organism
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
can escape the confines of the immediate tissue via the
circulatory system
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
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. When lymph nodes cannot destroy all pathogens, the infection spreads further. 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
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
, the term
sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
is applied, with the terms
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 is characterized by high systemic levels of
acute-phase protein
Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the ''acute- ...
s. 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, which cause a range of systemic effects including:
*
Fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
* Increased
blood pressure
* Decreased
sweating
Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals.
Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distri ...
*
Malaise
*
Loss of appetite
*
Somnolence
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 microliter, but extreme cases can see it approach 100 000 cells per microliter.
Bacterial infection usually results in an increase of
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s, creating
neutrophilia
Neutrophilia (also called neutrophil leukocytosis or occasionally neutrocytosis) is leukocytosis of neutrophils, that is, a high number of neutrophils in the blood. Because neutrophils are the main type of granulocytes, mentions of granulocytos ...
, whereas diseases such as
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
,
hay fever, and parasite infestation result in an increase in
eosinophils, creating
eosinophilia.
*
Leukopenia
Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of ...
can be induced by certain infections and diseases, including viral infection, ''
Rickettsia'' infection, some
protozoa,
tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, ...
, and some
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s.
Interleukins and obesity
With the discovery of
interleukins (IL), the concept of
systemic inflammation
Chronic systemic inflammation (SI) is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions s ...
developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
and other organ systems.
Chronic inflammation is widely observed in
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
.
Obese people commonly have many elevated markers of inflammation, including:
*
IL-6 (Interleukin-6)
Low-grade chronic inflammation is characterized by a two- to threefold increase in the systemic concentrations of cytokines such as TNF-α, IL-6, and CRP. Waist circumference correlates significantly with systemic inflammatory response.
Loss of
white adipose tissue reduces levels of inflammation markers.
As of 2017 the association of systemic inflammation with
insulin resistance and
type 2 diabetes, and with
atherosclerosis was under preliminary research, although rigorous
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s had not been conducted to confirm such relationships.
C-reactive protein (CRP) is generated at a higher level in obese people, and may increase the risk for
cardiovascular diseases.
Outcomes
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. Such is usually the outcome when limited or short-lived inflammation has occurred.
#
FibrosisLarge amounts of tissue destruction, or damage in tissues unable to regenerate, cannot 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. As a consequence, 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
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
and
pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
, do not follow this convention. More examples are available at
List of types of inflammation.
File:Acute_Appendicitis.jpg, Acute appendicitis
Appendicitis is inflammation of the appendix. Symptoms commonly include right lower abdominal pain, nausea, vomiting, and decreased appetite. However, approximately 40% of people do not have these typical symptoms. Severe complications of a r ...
File:Dermatitis.jpg, Acute dermatitis
Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved c ...
File:Streptococcus pneumoniae meningitis, gross pathology 33 lores.jpg, Acute infective meningitis
File:Tonsillitis.jpg, Acute tonsillitis
Tonsillitis is inflammation of the tonsils in the upper part of the throat. It can be acute or chronic. Acute tonsillitis typically has a rapid onset. Symptoms may include sore throat, fever, enlargement of the tonsils, trouble swallowing, a ...
See also
Notes
References
External links
*
{{Authority control
Immunology
Animal physiology
Inflammations
Human physiology