Anallergic reaction tocefaclor has led to inflammation of the skin on the foot. The cardinal signs of inflammation include: pain, heat, redness, swelling, and loss of function. Some of these indicators can be seen here.
Inflammation (fromLatin:inflammatio) is part of the biological response of body tissues to harmful stimuli, such aspathogens, damaged cells, orirritants. The fivecardinal signs are heat, pain, redness, swelling, andloss of function (Latincalor,dolor,rubor,tumor, andfunctio laesa).
Inflammation is a generic response, and therefore is considered a mechanism ofinnate immunity, whereasadaptive immunity is specific to each pathogen.[1] It is part of the biological response of body tissues to harmful stimuli, such aspathogens, damaged cells, orirritants.[2]
Inflammation is a protective response involvingimmune cells,blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out damaged cells and tissues, and initiate tissue repair. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. However inflammation can also have negative effects.[3] Too much inflammation, in the form of chronic inflammation, is associated with various diseases, such ashay fever,periodontal disease,atherosclerosis, andosteoarthritis.
Inflammation can be classified asacute orchronic. Acute inflammation is the initial response of the body to harmful stimuli, and is achieved by the increased movement ofplasma andleukocytes (in particulargranulocytes) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the localvascular system, theimmune system, and various cells in the injured tissue. Prolonged inflammation, known aschronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such asmononuclear cells, and involves simultaneous destruction andhealing of the tissue.
Inflammation has also been classified as Type 1 and Type 2 based on the type ofcytokines andhelper T cells (Th1 and Th2) involved.[4]
The earliest known reference for the term inflammation is around the early 15th century. The word root comes fromOld Frenchinflammation around the 14th century, which then comes fromLatininflammatio orinflammationem. Literally, the term relates to the word "flame", as the property of being "set on fire" or "to burn".[5]
The terminflammation is not a synonym forinfection.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 in discussion of infection, and the word is used to imply a microbial invasive cause for the observed inflammatory reaction.Inflammation, on the other hand, describes just the body's immunovascular response, regardless of cause. But, because the two are oftencorrelated, words ending in the suffix-itis (which means inflammation) are sometimes informally described as referring to infection: for example, the wordurethritis strictly means only "urethral inflammation", but clinicalhealth 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 is crucial in situations inpathology andmedical diagnosis that involve inflammation that is not driven by microbial invasion, such as cases ofatherosclerosis,trauma,ischemia, andautoimmune diseases (includingtype III hypersensitivity).
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.[9] 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.[10]
Acute inflammation occurs immediately upon injury, lasting only a few days.[11]Cytokines andchemokines promote the migration ofneutrophils andmacrophages to the site of inflammation.[11] Pathogens, allergens, toxins, burns, and frostbite are some of the typical causes of acute inflammation.[11]Toll-like receptors (TLRs) recognize microbial pathogens.[11] Acute inflammation can be a defensive mechanism to protect tissues against injury.[11] Inflammation lasting 2–6 weeks is designated subacute inflammation.[11][12]
Pain is due to the release of chemicals such as bradykinin and histamine that stimulate nerve endings.[15] Acute inflammation of the lung (usually in response topneumonia) does not cause pain unless the inflammation involves theparietal pleura, which does havepain-sensitive nerve endings.[15] Heat and redness are due to increased blood flow at body core temperature to the inflamed site. Swelling is caused by accumulation of fluid.
The fifth sign,loss of function, is believed to have been added later byGalen,[19]Thomas Sydenham[20] orRudolf Virchow.[9][15][16] Examples of loss of function include pain that inhibits mobility, severe swelling that prevents movement, having a worse sense of smell during a cold, or having difficulty breathing when bronchitis is present.[21][22] Loss of function has multiple causes.[15]
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) ofplasma proteins and fluid into the tissue (edema), which manifests itself as swelling (tumor). Some of the released mediators such asbradykinin increase the sensitivity to pain (hyperalgesia,dolor). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainlyneutrophils andmacrophages, to flow out of the blood vessels (extravasation) and into the tissue. The neutrophils migrate along achemotactic gradient created by the local cells to reach the site of injury.[9] 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 thecomplement system activated by bacteria and thecoagulation andfibrinolysis systems activated bynecrosis (e.g., burn, trauma).[9]
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.[9]
As defined, acute inflammation is an immunovascular response to inflammatory stimuli, which can include infection or trauma.[24][25] 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 myeloidgranulocytes in the acute setting).[24] The vascular component of acute inflammation involves the movement ofplasma fluid, containing importantproteins such asfibrin andimmunoglobulins (antibodies), into inflamed tissue.
Upon contact with PAMPs, tissuemacrophages andmastocytes release vasoactive amines such ashistamine andserotonin, as well aseicosanoids such asprostaglandin E2 andleukotriene B4 to remodel the local vasculature.[26] Macrophages and endothelial cells releasenitric oxide.[27] These mediators vasodilate and permeabilize theblood vessels, which results in the net distribution ofblood plasma from the vessel into the tissue space. The increased collection of fluid into the tissue causes it to swell (edema).[26] This exuded tissue fluid contains various antimicrobial mediators from the plasma such ascomplement,lysozyme,antibodies, which can immediately deal damage to microbes, andopsonise the microbes in preparation for the cellular phase. If the inflammatory stimulus is a lacerating wound, exudedplatelets,coagulants,plasmin andkinins canclot the wounded area using vitamin K-dependent mechanisms[28] and providehaemostasis in the first instance. These clotting mediators also provide a structural staging framework at the inflammatory tissue site in the form of afibrin lattice – as would constructionscaffolding at a construction site – for the purpose of aiding phagocytic debridement andwound repair later on. Some of the exuded tissue fluid is also funneled bylymphatics to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of theadaptive immune system.
Infectedingrown toenail showing the characteristic redness and swelling associated with acute inflammation
Acute inflammation is characterized by marked vascular changes, includingvasodilation, increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators.[26] Vasodilation occurs first at thearteriole level, progressing to thecapillary 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 ofplasma into the tissues, with resultantstasis due to the increase in the concentration of the cells within blood – a condition characterized by enlarged vessels packed with cells. Stasis allowsleukocytes to marginate (move) along theendothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as theshearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.
Thekinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.
Thecoagulation system orclotting cascade, which forms a protective protein mesh over sites of injury.
Thefibrinolysis system, which acts in opposition to thecoagulation system, to counterbalance clotting and generate several other inflammatory mediators.
Cleaves to produceC3a andC3b. C3a stimulates histamine release by mast cells, thereby producing vasodilation. C3b is able to bind to bacterial cell walls and act as anopsonin, which marks the invader as a target forphagocytosis.
Stimulates histamine release by mast cells, thereby producing vasodilation. It is also able to act as achemoattractant to direct cells via chemotaxis to the site of inflammation.
A protein that circulates inactively, until activated by collagen, platelets, or exposedbasement membranes viaconformational change. When activated, it in turn is able to activate three plasma systems involved in inflammation: the kinin system, fibrinolysis system, and coagulation system.
A complex of the complement proteinsC5b,C6,C7,C8, and multiple units ofC9. The combination and activation of this range of complement proteins forms themembrane attack complex, which is able to insert into bacterial cell walls and causes cell lysis with ensuing bacterial death.
Cleaves the soluble plasma proteinfibrinogen to produce insolublefibrin, which aggregates to form ablood clot. Thrombin can also bind to cells via thePAR1 receptor to trigger several other inflammatory responses, such as production ofchemokines andnitric oxide.
Thecellular component involvesleukocytes, which normally reside in blood and must move into the inflamed tissue viaextravasation to aid in inflammation.[24] Some act asphagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymaticgranules that damage pathogenic invaders. Leukocytes also release inflammatory mediators that develop and maintain the inflammatory response. In general, acute inflammation is mediated bygranulocytes, whereas chronic inflammation is mediated by mononuclear cells such asmonocytes andlymphocytes.
Neutrophils migrate from blood vessels to the infected tissue via chemotaxis, where they remove pathogens through phagocytosis and degranulationInflammation is a process by which the body's white blood cells and substances they produce protect us from infection with foreign organisms, such as bacteria and viruses. The (phagocytes) white blood cells are a nonspecific immune response, meaning that they attack any foreign bodies. However, in some diseases, like arthritis, the body's defense system the immune system triggers an inflammatory response when there are no foreign invaders to fight off. In these diseases, called autoimmune diseases, the body's normally protective immune system causes damage to its own tissues. The body responds as if normal tissues are infected or somehow abnormal.
Variousleukocytes, 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 asextravasation 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.[29] Activated macrophages in the tissue releasecytokines such asIL-1 andTNFα, which in turn leads to production ofchemokines that bind toproteoglycans forming gradient in the inflamed tissue and along theendothelial wall.[26] Inflammatory cytokines induce the immediate expression ofP-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 ofE-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression ofintegrin ligands such asICAM-1 andVCAM-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 aftersignal transduction via respectiveG 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 ofdiapedesis: 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.[29]
Movement of leukocytes within the tissue viachemotaxis: Leukocytes reaching the tissue interstitium bind toextracellular matrix proteins via expressed integrins andCD44 to prevent them from leaving the site. A variety of molecules behave aschemoattractants, for example, C3a or C5a (theanaphylatoxins), and cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.
Upon endocytic PRR binding,actin-myosincytoskeletal rearrangement adjacent to the plasma membrane occurs in a way thatendocytoses the plasma membrane containing the PRR-PAMP complex, and the microbe.Phosphatidylinositol andVps34-Vps15-Beclin1 signalling pathways have been implicated to traffic the endocytosed phagosome to intracellularlysosomes, where fusion of the phagosome and the lysosome produces a phagolysosome. Thereactive oxygen species,superoxides andhypochlorite bleach within the phagolysosomes then kill microbes inside the phagocyte.
Phagocytic efficacy can be enhanced byopsonization. Plasma derived complementC3b 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 expressopsonin receptorsFc receptor andcomplement 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 thelysosomal elimination of the infective agent.
These cells contain a large variety of enzymes that perform a number of functions. Granules can be classified as eitherspecific orazurophilic depending upon the contents, and are able to break down a number of substances, some of which may be plasma-derived proteins that allow these enzymes to act as inflammatory mediators.
Stored in preformed granules, histamine is released in response to a number of stimuli. It causesarteriole dilation, increasedvenous permeability, and a wide variety of organ-specific effects.
Antiviral, immunoregulatory, and anti-tumour properties. This interferon was originally called macrophage-activating factor, and is especially important in the maintenance of chronic inflammation.
Pro-inflammatory cytokine secreted by macrophages in response topathogen-associated molecular patterns (PAMPs); pro-inflammatory cytokine secreted by adipocytes, especially in obesity; anti-inflammatory myokine secreted by skeletal muscle cells in response to exercise.
Able to mediate leukocyte adhesion and activation, allowing them to bind to the endothelium and migrate across it. In neutrophils, it is also a potent chemoattractant, and is able to induce the formation of reactive oxygen species and the release of lysosomal enzymes by these cells.
These threeCysteine-containing leukotrienes contract lung airways, increase micro-vascular permeability, stimulate mucus secretion, and promote eosinophil-based inflammation in the lung, skin, nose, eye, and other tissues.
Potent stimulator of neutrophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation; monocyte chemotaxis; and with even greater potency eosinophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation.
Metabolic precursor to 5-Oxo-eicosatetraenoic acid, it is a less potent stimulator of neutrophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation; monocyte chemotaxis; and eosinophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation.
Potent vasodilator, relaxes smooth muscle, reduces platelet aggregation, aids in leukocyte recruitment, direct antimicrobial activity in high concentrations.
Both affect a wide variety of cells to induce many similar inflammatory reactions: fever, production of cytokines, endothelial gene regulation, chemotaxis, leukocyte adherence, activation offibroblasts. Responsible for the systemic effects of inflammation, such as loss of appetite and increased heart rate. TNF-α inhibits osteoblast differentiation.
Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on anepithelial surface, orpyogenic bacteria are involved.
Granulomatous inflammation: Characterised by the formation ofgranulomas, they are the result of a limited but diverse number of diseases, which include among otherstuberculosis,leprosy,sarcoidosis, andsyphilis.
Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allowsfibrin to pass through the blood vessels. If an appropriateprocoagulative stimulus is present, such as cancer cells,[9] a fibrinous exudate is deposited. This is commonly seen inserous 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 ofpus, which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such asstaphylococci is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are calledabscesses.
Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced bymesothelial cells ofserous membranes, but may be derived from blood plasma. Skinblisters exemplify this pattern of inflammation.
Ulcerative inflammation: Inflammation occurring near an epithelium can result in thenecrotic loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as anulcer.
Asthma is considered an inflammatory-mediated disorder. On the right is an inflamed airway due to asthma.Colitis (inflammation of the colon) caused byCrohn's disease.
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 bothallergic reactions and somemyopathies, with manyimmune system disorders resulting in abnormal inflammation. Non-immune diseases with causal origins in inflammatory processes include cancer,atherosclerosis, andischemic heart disease.[9]
Examples of disorders associated with inflammation include:
Atherosclerosis, formerly considered alipid storage disorder, is now understood as a chronic inflammatory condition involving the arterial walls.[33] Research has established a fundamental role for inflammation in mediating all stages of atherosclerosis from initiation through progression and, ultimately, the thrombotic complications from it.[33] These new findings reveal links between traditional risk factors like cholesterol levels and the underlying mechanisms ofatherogenesis.
Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to people.[33] For instance, elevation in markers of inflammation predicts outcomes of people withacute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory markerC-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors, such as LDL levels.[34][33]
Moreover, certain treatments that reduce coronary risk also limit inflammation. Notably, lipid-lowering medications such asstatins have shown anti-inflammatory effects, which may contribute to their efficacy beyond just lowering LDL levels.[35] This emerging understanding of inflammation's role in atherosclerosis has had significant clinical implications, influencing both risk stratification and therapeutic strategies.
Recent developments in the treatment of atherosclerosis have focused on addressing inflammation directly. New anti-inflammatory drugs, such as monoclonal antibodies targeting IL-1β, have been studied in large clinical trials, showing promising results in reducing cardiovascular events.[36] These drugs offer a potential new avenue for treatment, particularly for patients who do not respond adequately to statins. However, concerns about long-term safety and cost remain significant barriers to widespread adoption.
Inflammatory processes can be triggered by negative cognition or their consequences, such as stress, violence, or deprivation. Negative cognition may therefore contribute to inflammation, which in turn can lead to depression. A 2019 meta-analysis found that chronic inflammation is associated with a 30% increased risk of developingmajor depressive disorder, supporting the link between inflammation andmental health.[37]
An allergic reaction, formally known astype 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation, vasodilation, and nerve irritation. A common example ishay fever, which is caused by a hypersensitive response bymast cells toallergens. Pre-sensitised mast cells respond bydegranulating, releasingvasoactive 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.[9] Severe inflammatory response may mature into a systemic response known asanaphylaxis.
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.[9] Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria (Chédiak–Higashi syndrome), or producemicrobicides (chronic granulomatous disease). In addition, diseases affecting thebone marrow may result in abnormal or few leukocytes.
Certain drugs or exogenous chemical compounds are known to affect inflammation.Vitamin A deficiency, for example, causes an increase in inflammatory responses,[38] andanti-inflammatory drugs work specifically by inhibiting the enzymes that produce inflammatoryeicosanoids. Additionally, certain illicit drugs such ascocaine andecstasy may exert some of their detrimental effects by activating transcription factors intimately involved with inflammation (e.g.NF-κB).[39][40]
Inflammation orchestrates themicroenvironment around tumours, contributing to proliferation, survival and migration.[41] Cancer cells useselectins,chemokines and their receptors for invasion, migration and metastasis.[42] On the other hand, many cells of the immune system contribute tocancer immunology, suppressing cancer.[43]Molecular intersection between receptors of steroid hormones, which have important effects on cellular development, and transcription factors that play key roles in inflammation, such asNF-κB, may mediate some of the most critical effects of inflammatory stimuli on cancer cells.[44] 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.
There is some evidence from 2009 to suggest that cancer-related inflammation (CRI) may lead to accumulation of random genetic alterations in cancer cells.[45][needs update]
In 1863,Rudolf Virchow hypothesized that the origin of cancer was at sites of chronic inflammation.[42][46] As of 2012, chronic inflammation was estimated to contribute to approximately 15% to 25% of human cancers.[46][47]
An inflammatory mediator is a messenger that acts on blood vessels and/or cells to promote an inflammatory response.[48] Inflammatory mediators that contribute to neoplasia includeprostaglandins, inflammatorycytokines such asIL-1β,TNF-α,IL-6 andIL-15 andchemokines such asIL-8 andGRO-alpha.[49][46] These inflammatory mediators, and others, orchestrate an environment that fosters proliferation and survival.[42][49]
Inflammation also causes DNA damages due to the induction ofreactive oxygen species (ROS) by various intracellular inflammatory mediators.[42][49][46] In addition,leukocytes and otherphagocytic cells attracted to the site of inflammation induce DNA damages in proliferating cells through their generation of ROS andreactive nitrogen species (RNS). ROS and RNS are normally produced by these cells to fight infection.[42] ROS, alone, cause more than 20 types of DNA damage.[50] Oxidative DNA damages cause bothmutations[51] and epigenetic alterations.[52][46][53] RNS can also cause mutagenic DNA damages.[54]
A normal cell may undergocarcinogenesis to become a cancer cell if it is frequently subjected to DNA damage during long periods of chronic inflammation. DNA damages may cause geneticmutations due toinaccurate repair. In addition, mistakes in the DNA repair process may causeepigenetic alterations.[46][49][53] 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 incoding regions, 10–20 of which are"driver mutations" that contribute to cancer development.[46] However, chronic inflammation also causes epigenetic changes such asDNA methylations, that are often more common than mutations. Typically, several hundreds to thousands of genes are methylated in a cancer cell (seeDNA methylation in cancer). Sites of oxidative damage inchromatin can recruit complexes that containDNA methyltransferases (DNMTs), a histone deacetylase (SIRT1), and ahistone methyltransferase (EZH2), and thus induce DNA methylation.[46][55][56] DNA methylation of aCpG island in apromoter region may cause silencing of its downstream gene (seeCpG site andregulation of transcription in cancer). DNA repair genes, in particular, are frequently inactivated by methylation in various cancers (seehypermethylation of DNA repair genes in cancer). A 2018 report[57] 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).[58] However, mutations and epigenetic alterations were of roughly equal importance in generating esophageal squamous cell cancers (associated withtobacco chemicals andacetaldehyde, a product of alcohol metabolism).
It has long been recognized that infection withHIV is characterized not only by development of profoundimmunodeficiency but also by sustained inflammation and immune activation.[59][60][61] A substantial body of evidence implicates chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency.[59][62] Many now regard HIV infection not only as an evolving virus-induced immunodeficiency, but also as chronic inflammatory disease.[63] Even after the introduction ofeffective 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, thesooty mangabey, causes high-level viral replication but limited evidence of disease.[64][65] This lack of pathogenicity is accompanied by a lack of inflammation, immune activation and cellular proliferation. In sharp contrast, experimentalSIVsm infection ofrhesus macaque produces immune activation and AIDS-like disease with many parallels to human HIV infection.[66]
Delineating howCD4 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. Recent studies demonstrated thatcaspase-1-mediatedpyroptosis, a highly inflammatory form of programmed cell death, drives CD4 T-cell depletion and inflammation by HIV.[67][68][69] These are the two signature events that propel HIV disease progression toAIDS. 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.[70] 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 asIL-1β andIL-18 can be blocked in HIV-infected human lymphoid tissues by addition of the caspase-1 inhibitor VX-765,[67] which has already proven to be safe and well tolerated in phase II human clinical trials.[71] 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.
The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues.[9] 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:[9][72]
Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues,granulocytes promote the switch ofarachidonic acid–derivedprostaglandins andleukotrienes to lipoxins, which initiate the termination sequence.Neutrophil recruitment thus ceases and programmed death byapoptosis is engaged. These events coincide with the biosynthesis, fromomega-3 polyunsaturated fatty acids, ofresolvins andprotectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. As a consequence, apoptotic neutrophils undergophagocytosis bymacrophages, leading to neutrophil clearance and release of anti-inflammatory and reparativecytokines such as transforming growth factor-β1. The anti-inflammatory program ends with the departure of macrophages through thelymphatics.[83]
There is evidence for a link betweeninflammation and depression.[84] 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.[85][86][dubious –discuss]In addition, there is increasing evidence that inflammation can cause depression because of the increase of cytokines, setting the brain into a "sickness mode".[87]
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.[88] 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.[89]Inflammations that lead to serious depression could be caused by common infections such as those caused by a virus, bacteria or even parasites.[90]
There is evidence for a link between inflammation anddelirium based on the results of a recent longitudinal study investigating CRP in COVID-19 patients.[91]
Aninfectious organism can escape the confines of the immediate tissue via thecirculatory system orlymphatic 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 nearbylymph vessels. An infection of the lymph vessels is known aslymphangitis, and infection of a lymph node is known aslymphadenitis. 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, the termsepsis is applied, with the termsbacteremia being applied specifically for bacterial sepsis andviremia specifically to viral sepsis.Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead toseptic shock and death.[92]
Inflammation also is characterized by high systemic levels ofacute-phase proteins. In acute inflammation, these proteins prove beneficial; however, in chronic inflammation, they can contribute toamyloidosis.[9] These proteins includeC-reactive protein,serum amyloid A, andserum amyloid P, which cause a range of systemic effects including:[9]
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.[9] Bacterial infection usually results in an increase ofneutrophils, creatingneutrophilia, whereas diseases such asasthma,hay fever, and parasite infestation result in an increase ineosinophils, creatingeosinophilia.[9]
With the discovery ofinterleukins (IL), the concept ofsystemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves theendothelium and other organ systems.
Chronic inflammation is widely observed inobesity.[93][94] Obese people commonly have many elevated markers of inflammation, including:[95][96]
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.[99] Waist circumference correlates significantly with systemic inflammatory response.[100]
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:[9]
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 damagedparenchymal 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. Fibrousscarring occurs in these areas of damage, forming a scar composed primarily ofcollagen. The scar will not contain any specialized structures, such asparenchymal 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 achronic 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 thetoxins they release—includingreactive 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.
Inflammation is usually indicated by adding the suffix "itis", as shown below. However, some conditions, such asasthma andpneumonia, do not follow this convention. More examples are available atList of types of inflammation.
^All these signs may be observed in specific instances, but no single sign must, as a matter of course, be present.[13]These are the original, orcardinal signs of inflammation.[13]
^Functio laesa is an antiquated notion, as it is not unique to inflammation and is a characteristic of many disease states.[14]
^Abbas AB, Lichtman AH (2009). "Ch.2 Innate Immunity".Basic Immunology. Functions and disorders of the immune system (3rd ed.). Saunders/Elsevier.ISBN978-1-4160-4688-2.
^abcdefPahwa R, Goyal A, Bansal P, Jialal I (7 August 2023)."Chronic inflammation". StatPearls, US National Library of Medicine.PMID29630225. Retrieved29 December 2024.
^abStedman's Medical Dictionary (Twenty-fifth ed.). Williams & Wilkins. 1990.
^Porth C (2007).Essentials of pahtophysiology: concepts of altered health states. Hagerstown, MD: Lippincott Williams & Wilkins. p. 270.ISBN978-0-7817-7087-3.
^abHerrington S (2014).Muir's Textbook of Pathology (15th ed.). CRC Press. p. 59.ISBN978-1-4441-8499-0.
^Carstens E, Akiyama T, Cevikbas F, Kempkes C, Buhl T, Mess C, et al. (2014). "Role of Interleukin-31 and Oncostatin M in Itch and Neuroimmune Communication". In Carstens M, Akiyama T (eds.).Itch: Mechanisms and Treatment. Frontiers in Neuroscience. Boca Raton (FL): CRC Press/Taylor & Francis.ISBN978-1-4665-0543-8.PMID24830021.
^Spagnoli LG, Bonanno E, Sangiorgi G, Mauriello A (November 2007). "Role of inflammation in atherosclerosis".Journal of Nuclear Medicine.48 (11):1800–1815.doi:10.2967/jnumed.107.038661.PMID17942804.
^Wiedermann U, Chen XJ, Enerbäck L, Hanson LA, Kahu H, Dahlgren UI (December 1996). "Vitamin A deficiency increases inflammatory responses".Scandinavian Journal of Immunology.44 (6):578–84.doi:10.1046/j.1365-3083.1996.d01-351.x.PMID8972739.S2CID3079540.
^Hargrave BY, Tiangco DA, Lattanzio FA, Beebe SJ (2003). "Cocaine, not morphine, causes the generation of reactive oxygen species and activation of NF-kappaB in transiently cotransfected heart cells".Cardiovascular Toxicology.3 (2):141–51.doi:10.1385/CT:3:2:141.PMID14501032.S2CID35240781.
^Montiel-Duarte C, Ansorena E, López-Zabalza MJ, Cenarruzabeitia E, Iraburu MJ (March 2004). "Role of reactive oxygen species, glutathione and NF-kappaB in apoptosis induced by 3,4-methylenedioxymethamphetamine ("Ecstasy") on hepatic stellate cells".Biochemical Pharmacology.67 (6):1025–33.doi:10.1016/j.bcp.2003.10.020.PMID15006539.
^Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, et al. (June 2009). "Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible?".BioEssays.31 (6):629–41.doi:10.1002/bies.200800138.PMID19382224.S2CID205469320.
^Raza Y, Khan A, Farooqui A, Mubarak M, Facista A, Akhtar SS, et al. (October 2014). "Oxidative DNA damage as a potential early biomarker of Helicobacter pylori associated carcinogenesis".Pathology & Oncology Research.20 (4):839–46.doi:10.1007/s12253-014-9762-1.PMID24664859.S2CID18727504.
^Ipp H, Zemlin A (February 2013). "The paradox of the immune response in HIV infection: when inflammation becomes harmful".Clinica Chimica Acta; International Journal of Clinical Chemistry.416:96–9.doi:10.1016/j.cca.2012.11.025.PMID23228847.
^Nasi M, Pinti M, Mussini C, Cossarizza A (October 2014). "Persistent inflammation in HIV infection: established concepts, new perspectives".Immunology Letters.161 (2):184–8.doi:10.1016/j.imlet.2014.01.008.hdl:11380/1048114.PMID24487059.
^Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, et al. (September 1999). "Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response".Nature Cell Biology.1 (5):260–6.doi:10.1038/12971.PMID10559937.S2CID37216623.
^Sato Y, Ohshima T, Kondo T (November 1999). "Regulatory role of endogenous interleukin-10 in cutaneous inflammatory response of murine wound healing".Biochemical and Biophysical Research Communications.265 (1):194–9.Bibcode:1999BBRC..265..194S.doi:10.1006/bbrc.1999.1455.PMID10548513.
^Serhan CN (August 2008). "Controlling the resolution of acute inflammation: a new genus of dual anti-inflammatory and proresolving mediators".Journal of Periodontology.79 (8 Suppl):1520–6.doi:10.1902/jop.2008.080231.PMID18673006.
^Headland SE, Norling LV (May 2015). "The resolution of inflammation: Principles and challenges".Seminars in Immunology.27 (3):149–60.doi:10.1016/j.smim.2015.03.014.PMID25911383.
^Greenhalgh DG (September 1998). "The role of apoptosis in wound healing".The International Journal of Biochemistry & Cell Biology.30 (9):1019–30.doi:10.1016/S1357-2725(98)00058-2.PMID9785465.
^Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, et al. (November 2005). "Regulation of lung injury and repair by Toll-like receptors and hyaluronan".Nature Medicine.11 (11):1173–9.doi:10.1038/nm1315.PMID16244651.S2CID11765495.
^Brietzke E, Stertz L, Fernandes BS, Kauer-Sant'anna M, Mascarenhas M, Escosteguy Vargas A, et al. (August 2009). "Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder".Journal of Affective Disorders.116 (3):214–7.doi:10.1016/j.jad.2008.12.001.PMID19251324.
^Ramanlal R, Gupta V (2021)."Physiology, Vasodilation".StatPearls. Treasure Island (FL): StatPearls Publishing.PMID32491494.Archived from the original on 11 May 2021. Retrieved22 September 2021.
^Choi J, Joseph L, Pilote L (March 2013). "Obesity and C-reactive protein in various populations: a systematic review and meta-analysis".Obesity Reviews.14 (3):232–44.doi:10.1111/obr.12003.PMID23171381.S2CID206227739.
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