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Inflammation (from la,
inflammatio
inflammatio
) is part of the complex biological response of body tissues to harmful stimuli, such as
pathogen In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms, ...
s, damaged cells, or irritants, and is a protective response involving
immune cells White blood cells (WBCs), also called leukocytes or leucocytes, are the cells of the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ...
,
blood vessels The blood vessels are the components of the circulatory system The circulatory system, also called the cardiovascular system or the vascular system, is an Biological system, organ system that permits blood to circulate and transport nutrien ...

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 Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
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 The innate immune system is one of the two main immunity strategies found in vertebrates (the other being the adaptive immune system). The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the dominant i ...

innate immunity
, as compared to
adaptive immunity The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, G ...
, 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 Allergic rhinitis, also known as hay fever, is a type of rhinitis, inflammation in the nose which occurs when the immune system overreacts to allergens in the air. Signs and symptoms include a runny or stuffy nose, sneezing, red, itchy, and wate ...
,
periodontal disease Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the Periodontium, tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen, red, and may bleed. It is considered the ...
,
atherosclerosis Atherosclerosis is a disease in which the wall of the artery An artery (plural arteries) () is a blood vessel that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated ...

atherosclerosis
, and
osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease An arthropathy is a disease of a joint. Signs and symptoms Arthralgia, Joint pain is a common but non-specific sign of joint disease. Signs will depend on the specific disease, and may ...

osteoarthritis
. 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 Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral) or heliotrope, a mineral aggregate * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood plasma ...
and
leukocyte White blood cells, also called leukocytes or leucocytes, are the of the that are involved in protecting the body against both and foreign invaders. All white blood cells are produced and derived from cells in the known as s. Leukocytes are ...
s (in particular
granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. They are also called polymorphonuclear leukocytes (PMN, PML, or PMNL) because of the varying shape of the cell nucleus, nucl ...
s) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local
vascular system The circulatory system, also called the cardiovascular system or the vascular system, is an organ system An organ system is a group of organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many o ...
, the
immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous system that embodies the Life#Biolog ...
, 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 damage or disease suffered by an organism, healing involves the repair of living tissue(s), organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ sy ...

healing
of the tissue from the inflammatory process. Inflammation has also been classified as Type 1 and Type 2 based on the type of
cytokines 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 autocrine ...
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 immune system, particularly in the adaptive immune system. As their name suggests, they "help" the activity of ...
(Th1 and Th2) involved. Inflammation is not a synonym for
infection An infection is the invasion of an organism's body by , their multiplication, and the reaction of tissues to the infectious agents and the s they produce. An infectious disease, also known as a transmissible disease or communicable disease, i ...

infection
. 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 , correlation or dependence is any statistical relationship, whether or not, between two s or . In the broadest sense correlation is any statistical association, though it actually refers to the degree to which a pair of variables are rel ...

correlated
, words ending in the suffix '' -itis'' (which refers to inflammation) are sometimes informally described as referring to infection. For example, the word ''
urethritis Urethritis is the inflammation 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 c ...
'' strictly means only "urethral inflammation", but clinical
health care provider A health care provider is an individual health professional A health professional (or healthcare professional) may provide health care Health care, health-care, or healthcare is the maintenance or improvement of health via the preventive healthca ...
s 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 causesCauses, or causality, is the relationship between one event and another. It may also refer to: * Causes (band), an indie band based in the Netherlands * Causes (company), an online company See also * Cau ...
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 medical sign, signs. It is most often referred to as diagnosis with the medicine, medical context being implici ...
where inflammation is not driven by microbial invasion, such as the cases of
atherosclerosis Atherosclerosis is a disease in which the wall of the artery An artery (plural arteries) () is a blood vessel that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated ...

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 injur ...
,
ischemia Ischemia or ischaemia is a restriction in blood Blood is a body fluid Body fluids, bodily fluids, or biofluids are liquid A liquid is a nearly incompressible fluid In physics, a fluid is a substance that continually Deformation ( ...
, and
autoimmune diseases An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. There are at least 80 types of autoimmune diseases. Nearly any body part can be involved. Common symptoms include low grade fever Fever, ...
(including
type III hypersensitivity Type III hypersensitivity occurs when there is accumulation of immune complexes (antigen In immunology, an antigen (Ag) is a molecule or molecular structure, such as may be present on the outside of a pathogen, that can be bound by an antigen ...
).


Causes


Types

*
Appendicitis Appendicitis is inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a pr ...

Appendicitis
*
Bursitis Bursitis is the inflammation of one or more Synovial bursa, bursae (fluid filled sacs) of synovial fluid in the body. They are lined with a synovial membrane that secretes a lubricating synovial fluid. There are more than 150 bursae in the human bo ...

Bursitis
*
Colitis Colitis is an inflammation 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 ...
*
Cystitis A urinary tract infection (UTI) is an infection An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to the ...
*
Dermatitis Dermatitis (also known as eczema) is inflammation of the skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle ...

Dermatitis
*
Epididymitis Epididymitis is a medical condition characterized by inflammation 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 prot ...
*
Encephalitis Encephalitis is inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a p ...
*
Gingivitis Gingivitis is a non-destructive disease that causes inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, o ...

Gingivitis
*
Meningitis Meningitis is an acute Acute may refer to: Science and technology * Acute angle ** Acute triangle ** Acute, a leaf shape in the glossary of leaf morphology#acute, glossary of leaf morphology * Acute (medicine), a disease that it is of short dur ...
*
Myelitis Myelitis is inflammation 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, ...
*
Nephritis Nephritis is inflammation of the kidneys and may involve the glomeruli, tubules, or interstitial tissue surrounding the glomeruli and tubules. Types * Glomerulonephritis is inflammation of the glomeruli. Glomerulonephritis is often implied ...
*
Neuritis Neuritis () is inflammation of a nerve or the general inflammation of the peripheral nervous system. Inflammation, and frequently concomitant Demyelinating disease, demyelination, cause impaired conduction of neural signals and leads to aberrant ne ...
*
Pancreatitis Pancreatitis is a condition characterized by inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irrit ...
*
Periodontitis Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the Periodontium, tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen, red, and may bleed. It is considered the ...
*
Pharyngitis Pharyngitis is inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a pr ...

Pharyngitis
*
Phlebitis Phlebitis or venitis is the inflammation 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 ...
*
Prostatitis Prostatitis is inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogen In biology Biology is the natural science that studies life and living org ...
* RSD/CRPS *
Rhinitis Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose A nose is a protuberance in vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multic ...
*
Sinusitis Sinusitis, also known as rhinosinusitis, is inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irrit ...

Sinusitis
*
Tendonitis Tendinopathy, also known as tendinitis or tendonitis, is a type of tendon A tendon or sinew is a tough band of fibrous connective tissue that connects muscle to bone A bone is a Stiffness, rigid tissue (anatomy), tissue that constitutes p ...
*
Tonsillitis Tonsillitis is inflammation of the tonsils in the upper part of the throat. Tonsillitis is a type of pharyngitis that typically comes on fast (rapid onset). Symptoms may include sore throat, fever, enlargement of the tonsils, trouble swallowing, a ...

Tonsillitis
*
Urethritis Urethritis is the inflammation 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 c ...
*
Vasculitis Vasculitis is a group of disorders that destroy blood vessel The blood vessels are the components of the circulatory system The circulatory system, also called the cardiovascular system or the vascular system, is an organ system that p ...
*
Vaginitis Vaginitis, also known as vulvovaginitis, is inflammation of the vagina In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vulva to the cervix. The outer vaginal opening is normall ...

Vaginitis


Acute

Acute inflammation occurs immediately upon injury, lasting only a few days.
Cytokine Cytokines are a broad and loose category of small protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and ...

Cytokine
s and
chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokine Cytokines are a broad and loose category of small protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid r ...
s promote the migration of
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. They are also called po ...

neutrophil
s and
macrophage Macrophages (abbreviated as Mφ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the ...

macrophage
s to the site of inflammation. Pathogens, allergens, toxins, burns, and frostbite are some of the typical causes of acute inflammation.
Toll-like receptor Toll-like receptors (TLRs) are a class of protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John ...
s (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.


Chronic

Chronic inflammation is inflammation that lasts for months or years. Macrophages,
lymphocytes A lymphocyte is a type of white blood cell in the immune system of gnathostomata, jawed vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated immunity, cell-mediated, cytotoxicity, cytotoxic innate immune system, i ...

lymphocytes
, and
plasma cells Plasma cells, also called plasma B cells, are white blood cells White blood cells (WBCs), also called leukocytes or leucocytes, are the cells of the immune system The immune system is a network of biological processes that protects an o ...

plasma cells
predominate in chronic inflammation, in contrast to the neutrophils that predominate in acute inflammation.
Diabetes Diabetes mellitus, commonly known as just diabetes, is a group of metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients such as proteins, fats, and carbohydrate ...
,
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart The heart is a cardiac muscle, muscular Organ (biology), organ in most animals, which pumps blood through the blood vessels of the circulatory system. The pumped ...
,
allergies Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, i ...

allergies
, and
chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease The lungs are the primary Organ (anatomy), organs of the respiratory system in humans and many other animals including a few fish and some snails. In mammal ...
(COPD) are examples of diseases mediated by chronic inflammation.
Obesity Obesity is a medical condition A disease is a particular abnormal condition that negatively affects the structure or function (biology), function of all or part of an organism, and that is not due to any immediate external injury. ...

Obesity
, smoking, stress, insufficient diet and poor 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, whereas 42% had more than one.


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 Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
: The traditional names for signs of inflammation come from Latin: * Dolor (
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain The International Association for the Study of Pain (IASP) is an international learned society A learned societ ...
) * Calor (
heat In thermodynamics Thermodynamics is a branch of physics that deals with heat, Work (thermodynamics), work, and temperature, and their relation to energy, entropy, and the physical properties of matter and radiation. The behavior of these ...

heat
) *
Rubor Flushing is to become markedly red in the face and often other areas of the skin, from various physiology, physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is m ...
(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 Inflammation (from la, inflammatio) is part of the complex biological response of ...
(loss of function) The first four (classical signs) were described by
Celsus Celsus (; grc-x-hellen, Κέλσος, ''Kélsos''; ''fl.'' 175–177 CE) was a 2nd-century Ancient Greek philosophy, Greek philosopher and Criticism of Christianity, opponent of early Christianity. His literary work, ''The True Word'' (al ...

Celsus
(ca. 30 BC–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 Linguistic anglicisation (or anglicization, occasionally anglification, anglifying, or Englishing) is the practice of modi ...
. However, the addition of this fifth sign has also been ascribed to
Thomas Sydenham Thomas Sydenham (10 September 1624 – 29 December 1689) was an English physician A physician (American English), medical practitioner (English in the Commonwealth of Nations, Commonwealth English), medical doctor, or simply doctor, is a ...

Thomas Sydenham
and . 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 Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain The International Association for the Study of Pain (IASP) is an international learned society A learned societ ...
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 Inflammatory may refer to: * Inflammation, a biological response to harmful stimuli * The word ''inflammatory'' is also used to refer literally to fire and flammability, and figuratively in relation to comments t ...

pneumonia
) does not cause pain unless the inflammation involves the
parietal pleura The pulmonary pleurae (''sing.'' pleura) are the two opposing layers of serous membrane In anatomy Anatomy (Greek ''anatomē'', 'dissection') is the branch of biology concerned with the study of the structure of organism In biology, ...
, 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 Mφ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the ...
,
dendritic cells Dendritic cells (DCs) are antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen In immunology, an antigen (Ag) is a molecule or molecular structure, such as may be present on the outside ...

dendritic cells
,
histiocytes A histiocyte is a vertebrate cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religious recluse lives * P ...
,
Kupffer cells Kupffer cells, also known as stellate macrophages and Kupffer–Browicz cells, are specialized cells localized in liver The liver is an organ only found in vertebrates which detoxifies various metabolites, synthesizes proteins and produces bi ...
and
mast cell#REDIRECT Mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem ...

mast cell
s. 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 t ...
s'' (PRRs), which recognize (i.e., bind) two subclasses of molecules:
pathogen-associated molecular patternPathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast array ...
s (PAMPs) and
damage-associated molecular pattern Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response The innate immune system is one of the two main immunity strategies found in vertebrates Vertebrates () comprise all spe ...
s (DAMPs). PAMPs are compounds that are associated with various
pathogen In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms, ...
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 Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral) or heliotrope, a mineral aggregate * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood plasma ...
proteins and fluid into the tissue (
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue Tissue may refer to: Biology * Tissue (biology), an ensemble of similar cells that together carry out a ...

edema
), which manifests itself as swelling (''tumor''). Some of the released mediators such as
bradykinin Bradykinin (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 Nitric oxide ( nitrogen oxide or nitrogen monoxide) ...

bradykinin
increase the sensitivity to pain (
hyperalgesia Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain Pain is a distressing feeling often caused by intense or damaging stimuli ...
, ''dolor''). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly
neutrophils 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 in ...

neutrophils
and
macrophages Macrophages (abbreviated as Mφ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the ...
, to flow out of the blood vessels (extravasation) and into the tissue. The neutrophils migrate along a
chemotactic Chemotaxis (from '' chemo-'' + '' taxis'') is the movement of an organism in response to a chemical stimulus. Somatic cells, bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biological cell. They ...
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 The complement system, also known as complement cascade, is a part of the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ὀργαν ...

complement system
activated by bacteria and the
coagulation Coagulation, also known as clotting, is the process by which blood Blood is a body fluid Body fluids, bodily fluids, or biofluids are liquid A liquid is a nearly incompressible In fluid mechanics or more generally continuum mech ...
and fibrinolysis systems activated by
necrosis Necrosis (from Ancient Greek wikt:νέκρωσις, νέκρωσις ''nékrōsis'' 'death') is a form of cell injury which results in the premature death of Cell (biology), cells in living Tissue (biology), tissue by Autolysis (biology), autol ...
(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.


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 Granulocytes are a category of white blood cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. They are also called polymorphonuclear leukocytes (PMN, PML, or PMNL) because of the varying shape ...
in the acute setting). The vascular component of acute inflammation involves the movement of plasma fluid, containing important
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
s such as
fibrin Fibrin (also called Factor Ia) is a fibrous Fiber or fibre (from la, fibra, links=no) is a natural Nature, in the broadest sense, is the natural, physical, material world or universe The universe ( la, universus) is all of ...
and
immunoglobulin An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystal ...

immunoglobulin
s (
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique mo ...

antibodies
), into inflamed tissue. Upon contact with PAMPs, tissue
macrophages Macrophages (abbreviated as Mφ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the ...
and mastocytes release vasoactive amines such as histamine 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 vessels, which results in the net distribution of blood plasma from the vessel into the tissue space. The increased collection of fluid into the tissue causes it to swell (
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue Tissue may refer to: Biology * Tissue (biology), an ensemble of similar cells that together carry out a ...

edema
). This exuded tissue fluid contains various antimicrobial mediators from the plasma such as complement system, complement, lysozyme,
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique mo ...

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, coagulation system, coagulants, plasmin and kinins can clot the wounded area and provide haemostasis in the first instance. These clotting mediators also provide a structural staging framework at the inflammatory tissue site in the form of a
fibrin Fibrin (also called Factor Ia) is a fibrous Fiber or fibre (from la, fibra, links=no) is a natural Nature, in the broadest sense, is the natural, physical, material world or universe The universe ( la, universus) is all of ...
lattice – as would construction scaffolding at a construction site – for the purpose of aiding phagocytic debridement and wound healing, 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. 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 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 Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral) or heliotrope, a mineral aggregate * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood plasma ...
into the tissues, with resultant Venous stasis, stasis due to the increase in the concentration of the cells within blood – a condition characterized 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 Shear stress, 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 The complement system, also known as complement cascade, is a part of the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ὀργαν ...

complement system
, when activated, creates a cascade of chemical reactions that promotes Antibody opsonization, opsonization, chemotaxis, and agglutination (biology), agglutination, and produces the Membrane attack complex, 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
leukocyte White blood cells, also called leukocytes or leucocytes, are the of the that are involved in protecting the body against both and foreign invaders. All white blood cells are produced and derived from cells in the known as s. Leukocytes are ...
s, 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 (cell biology), granules that damage pathogenic invaders. Leukocytes also release inflammatory mediators that develop and maintain the inflammatory response. In general, acute inflammation is mediated by
granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. They are also called polymorphonuclear leukocytes (PMN, PML, or PMNL) because of the varying shape of the cell nucleus, nucl ...
s, whereas chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.


Leukocyte extravasation

Various
leukocyte White blood cells, also called leukocytes or leucocytes, are the of the that are involved in protecting the body against both and foreign invaders. All white blood cells are produced and derived from cells in the known as s. Leukocytes are ...
s, 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 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 autocrine ...
such as Interleukin 1, IL-1 and TNFα, which in turn leads to production of
chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokine Cytokines are a broad and loose category of small protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid r ...
s that bind to proteoglycans forming gradient in the inflamed tissue and along the endothelial 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 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: 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 proteins via expressed integrins and CD44 to prevent them from leaving the site. A variety of molecules behave as chemoattractants, 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 (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 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 receptor (immunology), scavenger receptors binding to LPS. Upon endocytic PRR binding, actin-myosin cytoskeletal rearrangement adjacent to the plasma membrane occurs in a way that endocytoses the plasma membrane containing the PRR-PAMP complex, and the microbe. Phosphatidylinositol and Vps34-PIK3R4, Vps15-BECN1, 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 and hypochlorite bleach within the phagolysosomes then kill microbes inside the phagocyte. Phagocytic efficacy can be enhanced by opsonization. Plasma derived complement C3b 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 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, sarcoidosis, and syphilis. * Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows
fibrin Fibrin (also called Factor Ia) is a fibrous Fiber or fibre (from la, fibra, links=no) is a natural Nature, in the broadest sense, is the natural, physical, material world or universe The universe ( la, universus) is all of ...
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 membrane, 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), 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 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 (dermatology), 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 reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with causal origins in inflammatory processes include cancer,
atherosclerosis Atherosclerosis is a disease in which the wall of the artery An artery (plural arteries) () is a blood vessel that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated ...

atherosclerosis
, and ischaemic heart disease, ischemic heart disease. Examples of disorders associated with inflammation include: * Acne vulgaris * Asthma * Autoimmune diseases * Autoinflammatory diseases * Celiac disease * Asymptomatic inflammatory prostatitis, Chronic prostatitis * Ulcerative colitis, Colitis * Diverticulitis * Familial Mediterranean Fever * Glomerulonephritis * Hidradenitis suppurativa * Hypersensitivity, 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 Inflammatory may refer to: * Inflammation, a biological response to harmful stimuli * The word ''inflammatory'' is also used to refer literally to fire and flammability, and figuratively in relation to comments t ...

pneumonia
* Reperfusion injury * Rheumatic fever * Rheumatoid arthritis *
Rhinitis Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose A nose is a protuberance in vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multic ...
* Sarcoidosis * Transplant rejection *
Vasculitis Vasculitis is a group of disorders that destroy blood vessel The blood vessels are the components of the circulatory system The circulatory system, also called the cardiovascular system or the vascular system, is an organ system that p ...


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. 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 I hypersensitivity, type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation, vasodilation, and nerve irritation. A common example is
hay fever Allergic rhinitis, also known as hay fever, is a type of rhinitis, inflammation in the nose which occurs when the immune system overreacts to allergens in the air. Signs and symptoms include a runny or stuffy nose, sneezing, red, itchy, and wate ...
, which is caused by a hypersensitive response by
mast cell#REDIRECT Mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem ...

mast cell
s to allergens. Pre-sensitised mast cells respond by degranulation, 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.


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 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 microbicides (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 and Ecstasy (drug), 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 cytokines such as Interleukin 1 beta, IL-1β, tumor necrosis factor alpha, TNF-α, Interleukin 6, IL-6 and Interleukin 15, IL-15 and
chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokine Cytokines are a broad and loose category of small protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid r ...
s such as Interleukin 8, IL-8 and CXCL1, 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, White blood cell, leukocytes and other Phagocyte, 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 mutations and epigenetic alterations. RNS also cause mutagenic DNA damages. A normal cell may undergo carcinogenesis to become a cancer cell if it is frequently subjected to DNA damage during long periods of chronic inflammation. DNA damages may cause genetic mutations due to DNA repair#Translecion synthesis, inaccurate repair. In addition, mistakes in the DNA repair process may cause Cancer epigenetics, 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 carcinogenesis, “driver mutations” that contribute to cancer development. However, chronic inflammation also causes epigenetic changes such as DNA methylation in cancer, 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). Sites of oxidative damage in chromatin can recruit complexes that contain DNA methyltransferases (DNMTs), a histone deacetylase (sirtuin 1, SIRT1), and a EZH2, histone methyltransferase (EZH2), and thus induce DNA methylation. DNA methylation of a CpG site, CpG island in a Promoter (genetics), promoter region 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 DNA methylation in cancer#Likely role of hypermethylation of DNA repair genes in cancer, 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 Cigarette#Smokers, tobacco chemicals and Acetaldehyde#Carcinogenicity, 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 Antiretroviral therapy, highly active, 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: Simian immunodeficiency virus, 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 Simian immunodeficiency virus, SIVsm infection of rhesus macaque produces immune activation and AIDS-like disease with many parallels to human HIV infection. Delineating how CD4 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 Institute of Allergy and Infectious Diseases, National Institutes of Health. Recent studies demonstrated that Caspase 1, caspase-1-mediated pyroptosis, 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 HIV/AIDS, 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 Interleukin 1 beta, IL-1β and Interleukin 18, 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 (mood), 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 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. 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 an organism's body by , their multiplication, and the reaction of tissues to the infectious agents and the s they produce. An infectious disease, also known as a transmissible disease or communicable disease, i ...

infection
, the term sepsis 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 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, which cause a range of systemic effects including: * Fever * Increased blood pressure * Decreased sweating * Malaise * Anorexia (symptom), 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 granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. They are also called po ...

neutrophil
s, creating neutrophilia, whereas diseases such as asthma,
hay fever Allergic rhinitis, also known as hay fever, is a type of rhinitis, inflammation in the nose which occurs when the immune system overreacts to allergens in the air. Signs and symptoms include a runny or stuffy nose, sneezing, red, itchy, and wate ...
, 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.


Interleukins 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. Chronic inflammation is widely observed in obesity. Obese people commonly have many elevated markers of inflammation, including: * Interleukin-6, 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. The association of systemic inflammation with insulin resistance and type 2 diabetes, and with
atherosclerosis Atherosclerosis is a disease in which the wall of the artery An artery (plural arteries) () is a blood vessel that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated ...

atherosclerosis
is under preliminary research, although rigorous clinical trials have 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. # Fibrosis
Large 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 "wikt:-itis, itis", as shown below. However, some conditions, such as asthma and
pneumonia Pneumonia is an inflammatory Inflammatory may refer to: * Inflammation, a biological response to harmful stimuli * The word ''inflammatory'' is also used to refer literally to fire and flammability, and figuratively in relation to comments t ...

pneumonia
, do not follow this convention. More examples are available at List of types of inflammation. File:Acute_Appendicitis.jpg, Acute appendicitis File:Dermatitis.jpg, Acute dermatitis File:Streptococcus pneumoniae meningitis, gross pathology 33 lores.jpg, Acute infective meningitis File:Tonsillitis.jpg, Acute tonsillitis


See also


Notes


References


External links

* {{Authority control Immunology Animal physiology Inflammations Human physiology