Editing Fever (section)

===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>