Editing Fever (section)

==Mechanism==
{{See also|Thermoregulation in humans}}

===Hypothalamus===
Temperature is regulated in the [[hypothalamus]]. The trigger of a fever, called a pyrogen, results in the release of [[prostaglandin E2]] (PGE2). PGE2 in turn acts on the hypothalamus, which creates a systemic response in the body, causing heat-generating effects to match a new higher temperature set point. There are four receptors in which PGE2 can bind (EP1-4), with a previous study showing the EP3 subtype is what mediates the fever response.<ref>{{cite journal |vauthors=Ushikubi F et al. |date=September 1998 |title=Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3 |journal=Nature |volume=395 |issue=6699 |pages=281–284 |bibcode=1998Natur.395..281U |doi=10.1038/26233 |pmid=9751056 |s2cid=4420632}}</ref> Hence, the hypothalamus can be seen as working like a [[thermostat]].<ref name="Harrisons20th" /> When the set point is raised, the body increases its temperature through both active generation of heat and retention of heat. Peripheral [[vasoconstriction]] both reduces heat loss through the skin and causes the person to feel cold. [[Norepinephrine]] increases [[thermogenesis]] in [[brown adipose tissue]], and muscle contraction through shivering raises the [[Basal metabolic rate|metabolic rate]].<ref name="pmid25976513">{{cite journal |vauthors=Evans SS, Repasky EA, Fisher DT |date=June 2015 |title=Fever and the thermal regulation of immunity: the immune system feels the heat |journal=Nature Reviews. Immunology |volume=15 |issue=6 |pages=335–349 |doi=10.1038/nri3843 |pmc=4786079 |pmid=25976513}}</ref>

If these measures are insufficient to make the blood temperature in the brain match the new set point in the hypothalamus, the brain orchestrates heat effector mechanisms via the [[autonomic nervous system]] or primary motor center for shivering. These may be:<ref>{{Cite journal |last=Nakamura |first=Kazuhiro |date=November 2011 |title=Central circuitries for body temperature regulation and fever |url=https://www.physiology.org/doi/10.1152/ajpregu.00109.2011 |journal=American Journal of Physiology-Regulatory, Integrative and Comparative Physiology |language=en |volume=301 |issue=5 |pages=R1207–R1228 |doi=10.1152/ajpregu.00109.2011 |issn=0363-6119}}</ref><ref>{{Cite journal |last=Morrison |first=S.F. |last2=Nakamura |first2=K. |date=2019-02-10 |title=Central Mechanisms for Thermoregulation |url=https://www.annualreviews.org/doi/10.1146/annurev-physiol-020518-114546 |journal=Annual Review of Physiology |language=en |volume=81 |issue=1 |pages=285–308 |doi=10.1146/annurev-physiol-020518-114546 |issn=0066-4278}}</ref><ref>{{Cite journal |last=Nakamura |first=Kazuhiro |last2=Nakamura |first2=Yoshiko |last3=Kataoka |first3=Naoya |date=January 2022 |title=A hypothalamomedullary network for physiological responses to environmental stresses |url=https://www.nature.com/articles/s41583-021-00532-x |journal=Nature Reviews Neuroscience |language=en |volume=23 |issue=1 |pages=35–52 |doi=10.1038/s41583-021-00532-x |issn=1471-003X}}</ref>
* Increased heat production by increased [[muscle tone]], [[shivering]] (muscle movements to produce heat) and release of hormones like [[epinephrine]]; and
* Prevention of heat loss, e.g., through [[vasoconstriction]].
When the hypothalamic set point moves back to baseline—either spontaneously or via medication—normal functions such as sweating, and the reverse of the foregoing processes (e.g., vasodilation, end of shivering, and nonshivering heat production) are used to cool the body to the new, lower setting.{{citation needed|date=April 2020}}

This contrasts with [[hyperthermia]], in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat. Hyperthermia is usually the result of an excessively hot environment ([[heat stroke]]) or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to [[anti-pyretic]] medications.<ref name="Harrisons20th" />{{verify source|date=April 2020}}

In infants, the autonomic nervous system may also activate [[brown adipose tissue]] to produce heat (non-shivering thermogenesis).<ref>{{Cite journal |last1=Nowack |first1=Julia |last2=Giroud |first2=Sylvain |last3=Arnold |first3=Walter |last4=Ruf |first4=Thomas |date=2017-11-09 |title=Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy |journal=Frontiers in Physiology |volume=8 |page=889 |doi=10.3389/fphys.2017.00889 |issn=1664-042X |pmc=5684175 |pmid=29170642 |doi-access=free}}</ref>

Increased heart rate and vasoconstriction contribute to increased [[blood pressure]] in fever.<ref>{{Cite journal |last=Deussen |first=A. |date=September 2007 |title=[Hyperthermia and hypothermia. Effects on the cardiovascular system] |url=https://pubmed.ncbi.nlm.nih.gov/17554514/ |journal=Der Anaesthesist |volume=56 |issue=9 |pages=907–911 |doi=10.1007/s00101-007-1219-4 |issn=0003-2417 |pmid=17554514}}</ref>

===Pyrogens===
<!--WHERE SHOULD THIS GO?   The highly toxic [[metabolism]]-boosting supplement [[2,4-Dinitrophenol|2,4-dinitrophenol]] induces [[hyperthermia|high body temperature]] via the inhibition of [[Adenosine triphosphate|ATP]] production by [[mitochondria]], resulting in impairment of [[cellular respiration]]. Instead of producing ATP, the energy of the [[proton gradient]] is lost as heat.<ref name="pmid22351299">{{cite journal | vauthors = Yen M, Ewald MB | title = Toxicity of weight loss agents | journal = Journal of Medical Toxicology | volume = 8 | issue = 2 | pages = 145–152 | date = June 2012 | pmid = 22351299 | pmc = 3550246 | doi = 10.1007/s13181-012-0213-7 }}</ref>-->
A pyrogen is a substance that induces fever.<ref>{{cite book |last1=Hagel |first1=Lars |url=https://archive.org/details/handbookprocessc00hage |title=Handbook of Process Chromatography |last2=Jagschies |first2=Günter |last3=Sofer |first3=Gail |date=2008-01-01 |publisher=Academic Press |isbn=978-0-12-374023-6 |edition=2nd |pages=[https://archive.org/details/handbookprocessc00hage/page/n145 127]–145 |chapter=5 – Analysis |doi=10.1016/b978-012374023-6.50007-5 |url-access=limited |name-list-style=vanc}}</ref> In the presence of an infectious agent, such as bacteria, viruses, viroids, ''etc''., the immune response of the body is to inhibit their growth and eliminate them. The most common pyrogens are endotoxins, which are [[lipopolysaccharide]]s (LPS) produced by [[Gram-negative bacteria]] such as ''[[Escherichia coli|E. coli]].'' But pyrogens include non-endotoxic substances (derived from microorganisms other than gram-negative-bacteria or from chemical substances) as well.<ref>{{cite book |url=https://archive.org/details/biocompatibility00bout |title=Biocompatibility and Performance of Medical Devices |vauthors=Kojima K |date=2012-01-01 |publisher=Woodhead Publishing |isbn=978-0-85709-070-6 |editor-last=Boutrand |editor-first=Jean-Pierre |series=Woodhead Publishing Series in Biomaterials |pages=[https://archive.org/details/biocompatibility00bout/page/n434 404]–448 |chapter=17 – Biological evaluation and regulation of medical devices in Japan |doi=10.1533/9780857096456.4.404 |url-access=limited |s2cid=107630997}}</ref> The types of pyrogens include internal (endogenous) and external (exogenous) to the body.<ref>{{Citation |last=El-Radhi |first=A. Sahib |title=Pathogenesis of Fever |date=2018 |journal=Clinical Manual of Fever in Children |pages=53–68 |editor-last=El-Radhi |editor-first=A. Sahib |url=https://doi.org/10.1007/978-3-319-92336-9_3 |access-date=2024-06-26 |place=Cham |publisher=Springer International Publishing |doi=10.1007/978-3-319-92336-9_3 |isbn=978-3-319-92336-9 |pmc=7122269}}</ref>

The "pyrogenicity" of given pyrogens varies: in extreme cases, bacterial pyrogens can act as [[superantigens]] and cause rapid and dangerous fevers.<ref>{{Cite journal |last=Affairs |first=Office of Regulatory |date=2018-11-03 |title=Pyrogens, Still a Danger |url=https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-technical-guides/pyrogens-still-danger |journal=FDA}}</ref> <!--[[Depyrogenation]]--><!--OF WHAT? PATIENTS? PLASMA? SENTENCE NONSENSICAL AS IT STANDS--><!-- may be achieved through [[filtration]], [[distillation]], [[chromatography]], or inactivation.-->

====Endogenous====
Endogenous pyrogens are [[cytokine]]s released from [[monocyte]]s (which are part of the [[immune system]]).<ref>{{cite book |title=Veterinary Medicine |date=2017-01-01 |publisher=W.B. Saunders |isbn=978-0-7020-5246-0 |editor-last=Constable |editor-first=Peter D. |edition=11th |pages=43–112 |chapter=4 – General Systemic States |doi=10.1016/b978-0-7020-5246-0.00004-8 |editor2-last=Hinchcliff |editor2-first=Kenneth W. |editor3-last=Done |editor3-first=Stanley H. |editor4-last=Grünberg |editor4-first=Walter |name-list-style=vanc |s2cid=214758182}}</ref> In general, they stimulate chemical responses, often in the presence of an [[antigen]], leading to a fever. Whilst they can be a product of external factors like exogenous pyrogens, they can also be induced by internal factors like [[damage associated molecular pattern]]s such as cases like [[rheumatoid arthritis]] or lupus.<ref>{{cite journal |vauthors=Dinarello CA |date=2015-03-31 |title=The history of fever, leukocytic pyrogen and interleukin-1 |journal=Temperature |volume=2 |issue=1 |pages=8–16 |doi=10.1080/23328940.2015.1017086 |pmc=4843879 |pmid=27226996}}</ref>

Major endogenous pyrogens are [[interleukin 1]] (α and β)<ref name="boron-58">{{cite book |author=Stitt, John |url=https://books.google.com/books?id=unBlQgAACAAJ |title=Medical Physiology: A Cellular and Molecular Approach |publisher=Elsevier Saunders |year=2008 |isbn=9781416031154 |veditors=Boron WF, Boulpaep, EL |edition=2nd |location=Philadelphia |chapter=Chapter 59: Regulation of Body Temperature |access-date=2 April 2020 |url-access=subscription}}</ref>{{rp|1237–1248}} and [[interleukin 6]] (IL-6).<ref>{{Cite book |last=Murphy, Kenneth (Kenneth M.) |title=Janeway's immunobiology |others=Weaver, Casey |year=2017 |isbn=978-0-8153-4505-3 |edition=9th |location=New York |pages=118–119 |oclc=933586700}}</ref> Minor endogenous pyrogens include [[interleukin-8]], [[Lymphotoxin alpha|tumor necrosis factor-β]], [[macrophage inflammatory protein]]-α and macrophage inflammatory protein-β as well as [[interferon-α]], [[IFN-β|interferon-β]], and [[Interferon-gamma|interferon-γ]].<ref name="boron-58" />{{rp|1237–1248}} [[Tumor necrosis factor-α]] (TNF) also acts as a pyrogen, mediated by [[interleukin 1]] (IL-1) release.<ref>{{cite journal |vauthors=Stefferl A, Hopkins SJ, Rothwell NJ, Luheshi GN |date=August 1996 |title=The role of TNF-alpha in fever: opposing actions of human and murine TNF-alpha and interactions with IL-beta in the rat |journal=British Journal of Pharmacology |volume=118 |issue=8 |pages=1919–1924 |doi=10.1111/j.1476-5381.1996.tb15625.x |pmc=1909906 |pmid=8864524}}</ref> These cytokine factors are released into general circulation, where they migrate to the brain's [[circumventricular organ]]s where they are more easily absorbed than in areas protected by the [[blood–brain barrier]].<ref>{{Citation |last1=Kennedy |first1=Rachel H. |title=Neuroimmune Signaling: Cytokines and the CNS |date=2016 |work=Neuroscience in the 21st Century |pages=1–41 |editor-last=Pfaff |editor-first=Donald W. |url=https://doi.org/10.1007/978-1-4614-6434-1_174-1 |access-date=2024-06-26 |place=New York |publisher=Springer |doi=10.1007/978-1-4614-6434-1_174-1 |isbn=978-1-4614-6434-1 |last2=Silver |first2=Rae |editor2-last=Volkow |editor2-first=Nora D.}}</ref> The cytokines then bind to [[endothelium|endothelial receptor]]s on vessel walls to receptors on [[microglial cell]]s, resulting in activation of the [[arachidonic acid pathway]].<ref>{{Cite book |last=Eskilsson |first=Anna |title=Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever |date=2020 |publisher=Linköping University, Department of Biomedical and Clinical Sciences |isbn=978-91-7929-936-1 |location=Linköping}}</ref>

Of these, IL-1β, TNF, and IL-6 are able to raise the temperature setpoint of an organism and cause fever. These proteins produce a [[cyclooxygenase]] which induces the hypothalamic production of PGE2 which then stimulates the release of neurotransmitters such as [[cyclic adenosine monophosphate]] and increases body temperature.<ref>{{cite book |last1=Srinivasan |first1=Lakshmi |title=Fetal and Neonatal Physiology |last2=Harris |first2=Mary Catherine |last3=Kilpatrick |first3=Laurie E. |date=2017-01-01 |publisher=Elsevier |isbn=978-0-323-35214-7 |editor-last=Polin |editor-first=Richard A. |edition=5th |pages=1241–1254.e4 |chapter=128 – Cytokines and Inflammatory Response in the Fetus and Neonate |doi=10.1016/b978-0-323-35214-7.00128-1 |editor2-last=Abman |editor2-first=Steven H. |editor3-last=Rowitch |editor3-first=David H. |editor4-last=Benitz |editor4-first=William E. |name-list-style=vanc}}</ref>

==== Exogenous ====
Exogenous pyrogens are external to the body and are of microbial origin. In general, these pyrogens, including bacterial cell wall products, may act on Toll-like receptors in the hypothalamus and elevate the thermoregulatory setpoint.<ref>{{cite book |last1=Wilson |first1=Mary E. |title=Tropical Infectious Diseases: Principles, Pathogens and Practice |last2=Boggild |first2=Andrea K. |date=2011-01-01 |publisher=W.B. Saunders |isbn=978-0-7020-3935-5 |editor-last=Guerrant |editor-first=Richard L. |edition=3rd |pages=925–938 |chapter=130 – Fever and Systemic Symptoms |doi=10.1016/b978-0-7020-3935-5.00130-0 |editor2-last=Walker |editor2-first=David H. |editor3-last=Weller |editor3-first=Peter F. |name-list-style=vanc}}</ref>

An example of a class of exogenous pyrogens are bacterial [[lipopolysaccharide]]s (LPS) present in the cell wall of [[gram-negative bacteria]]. According to one mechanism of pyrogen action, an immune system protein, [[lipopolysaccharide-binding protein]] (LBP), binds to LPS, and the LBP–LPS complex then binds to a [[CD14]] receptor on a [[macrophage]]. The LBP-LPS binding to CD14 results in cellular synthesis and release of various endogenous [[cytokine]]s, e.g., interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNFα). A further downstream event is activation of the [[arachidonic acid pathway]].<ref>{{cite journal |vauthors=Roth J, Blatteis CM |date=October 2014 |title=Mechanisms of fever production and lysis: Lessons from experimental LPS fever |journal=Comprehensive Physiology |volume=4 |issue=4 |pages=1563–1604 |doi=10.1002/cphy.c130033 |isbn=9780470650714 |pmid=25428854}}</ref>

===Neural circuit mechanism with PGE2 action===
PGE2 release comes from the [[arachidonic acid]] pathway. This pathway (as it relates to fever), is mediated by the [[enzyme]]s [[phospholipase|phospholipase A2]] (PLA2), [[cyclooxygenase|cyclooxygenase-2]] (COX-2), and [[prostaglandin E2 synthase]]. These enzymes ultimately mediate the synthesis and release of PGE2.<ref>{{Cite journal |last=Samuelsson |first=Bengt |last2=Morgenstern |first2=Ralf |last3=Jakobsson |first3=Per-Johan |date=September 2007 |title=Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target |url=https://linkinghub.elsevier.com/retrieve/pii/S0031699724117267 |journal=Pharmacological Reviews |language=en |volume=59 |issue=3 |pages=207–224 |doi=10.1124/pr.59.3.1}}</ref>

PGE2 is the ultimate mediator of the febrile response. The setpoint temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the [[preoptic area]] (POA) through the [[prostaglandin E receptor 3]] (EP3).<ref>{{Cite journal |last=Nakamura |first=Kazuhiro |last2=Kaneko |first2=Takeshi |last3=Yamashita |first3=Yoko |last4=Hasegawa |first4=Hiroshi |last5=Katoh |first5=Hironori |last6=Ichikawa |first6=Atsushi |last7=Negishi |first7=Manabu |date=1999-01-29 |title=Immunocytochemical localization of prostaglandin EP3 receptor in the rat hypothalamus |url=https://linkinghub.elsevier.com/retrieve/pii/S0304394098009628 |journal=Neuroscience Letters |language=en |volume=260 |issue=2 |pages=117–120 |doi=10.1016/S0304-3940(98)00962-8}}</ref><ref name=":1">{{Cite journal |last=Nakamura |first=Kazuhiro |last2=Matsumura |first2=Kiyoshi |last3=Kaneko |first3=Takeshi |last4=Kobayashi |first4=Shigeo |last5=Katoh |first5=Hironori |last6=Negishi |first6=Manabu |date=2002-06-01 |title=The Rostral Raphe Pallidus Nucleus Mediates Pyrogenic Transmission from the Preoptic Area |url=https://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.22-11-04600.2002 |journal=The Journal of Neuroscience |language=en |volume=22 |issue=11 |pages=4600–4610 |doi=10.1523/JNEUROSCI.22-11-04600.2002 |issn=0270-6474 |pmc=6758794 |pmid=12040067}}</ref><ref>{{Cite journal |last=Lazarus |first=Michael |last2=Yoshida |first2=Kyoko |last3=Coppari |first3=Roberto |last4=Bass |first4=Caroline E |last5=Mochizuki |first5=Takatoshi |last6=Lowell |first6=Bradford B |last7=Saper |first7=Clifford B |date=September 2007 |title=EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses |url=https://www.nature.com/articles/nn1949 |journal=Nature Neuroscience |language=en |volume=10 |issue=9 |pages=1131–1133 |doi=10.1038/nn1949 |issn=1097-6256}}</ref><ref name=":2">{{Cite journal |last=Nakamura |first=Yoshiko |last2=Yahiro |first2=Takaki |last3=Fukushima |first3=Akihiro |last4=Kataoka |first4=Naoya |last5=Hioki |first5=Hiroyuki |last6=Nakamura |first6=Kazuhiro |date=2022-12-23 |title=Prostaglandin EP3 receptor–expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling |url=https://www.science.org/doi/10.1126/sciadv.add5463 |journal=Science Advances |language=en |volume=8 |issue=51 |doi=10.1126/sciadv.add5463 |issn=2375-2548 |pmc=9788766 |pmid=36563142}}</ref> EP3-expressing neurons in the POA innervate the [[dorsomedial hypothalamus]] (DMH),<ref>{{Cite journal |last=Nakamura |first=Yoshiko |last2=Nakamura |first2=Kazuhiro |last3=Matsumura |first3=Kiyoshi |last4=Kobayashi |first4=Shigeo |last5=Kaneko |first5=Takeshi |last6=Morrison |first6=Shaun F. |date=December 2005 |title=Direct pyrogenic input from prostaglandin EP3 receptor‐expressing preoptic neurons to the dorsomedial hypothalamus |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1460-9568.2005.04515.x |journal=European Journal of Neuroscience |language=en |volume=22 |issue=12 |pages=3137–3146 |doi=10.1111/j.1460-9568.2005.04515.x |issn=0953-816X |pmc=2441892 |pmid=16367780}}</ref><ref name=":3">{{Cite journal |last=Nakamura |first=Y. |last2=Nakamura |first2=K. |last3=Morrison |first3=S.F. |date=2009-06-30 |title=Different populations of prostaglandin EP3 receptor-expressing preoptic neurons project to two fever-mediating sympathoexcitatory brain regions |url=https://linkinghub.elsevier.com/retrieve/pii/S0306452209003960 |journal=Neuroscience |language=en |volume=161 |issue=2 |pages=614–620 |doi=10.1016/j.neuroscience.2009.03.041 |pmc=2857774 |pmid=19327390}}</ref> the rostral [[raphe]] pallidus nucleus in the [[medulla oblongata]] (rRPa),<ref name=":1" /><ref name=":3" /> and the [[paraventricular nucleus]] (PVN) of the [[hypothalamus]].<ref>{{Cite journal |last=Zhang |first=Zhi-Hua |last2=Yu |first2=Yang |last3=Wei |first3=Shun-Guang |last4=Nakamura |first4=Yoshiko |last5=Nakamura |first5=Kazuhiro |last6=Felder |first6=Robert B. |date=October 2011 |title=EP3 receptors mediate PGE2-induced hypothalamic paraventricular nucleus excitation and sympathetic activation |url=https://www.physiology.org/doi/10.1152/ajpheart.00262.2011 |journal=American Journal of Physiology-Heart and Circulatory Physiology |language=en |volume=301 |issue=4 |pages=H1559–H1569 |doi=10.1152/ajpheart.00262.2011 |issn=0363-6135 |pmc=3197370 |pmid=21803943}}</ref> Under normal conditions, EP3-expressing neurons in the POA are important [[Thermoregulation|thermoregulatory]] neurons, which provide continuous inhibitory signals with the transmitter [[GABA]] to control [[Sympathetic nervous system|sympathetic]] output neurons in the DMH and rRPa, thereby performing bidirectional regulation of basal body temperature.<ref name=":2" /> During infection, PGE2 produced in the brain inhibits the activity of EP3-expressing neurons in the POA to attenuate the inhibition of sympathetic output, and thereby activates the sympathetic output system, which evokes non-shivering thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body surface, leading to fever.<ref name=":2" /> It is presumed that the innervation from the POA to the PVN mediates the neuroendocrine effects of fever through the pathway involving [[pituitary gland]] and various [[endocrine organs]].