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{{Short description|Class of molecules found in the outer membrane of
{{distinguish|glycolipid}}
{{Use dmy dates|date=October 2022}}[[File:LPS.svg|thumb|200px|Structure of a lipopolysaccharide (LPS)]]
'''
Lipopolysaccharides can have substantial impacts on human health, primarily through interactions with the immune system. LPS is a potent activator of the immune system and is a [[Pyrogen (fever)|pyrogen]] (agent that causes fever).<ref name="
==Discovery==
The toxic activity of LPS was first discovered and termed ''endotoxin'' by [[Richard Friedrich Johannes Pfeiffer]]. He distinguished between [[exotoxins]], toxins that are released by bacteria into the surrounding environment, and endotoxins, which are toxins "within" the bacterial cell and released only after destruction of the bacterial outer membrane.<ref>{{Cite book |
== Functions in bacteria ==
LPS is a major component of the outer cell membrane of [[
==Composition==
[[File:Kdo2-lipidA.png|thumb|right|300px|The saccharolipid Kdo<sub>2</sub>-Lipid A. [[3-Deoxy-D-manno-oct-2-ulosonic acid|Kdo]] residues in {{red|red}} (core), glucosamine residues in {{blue|blue}}, acyl chains in {{black|black}} and phosphate groups in {{green|green}}.]]
=== O-antigen ===
The repetitive [[glycan]] [[polymer]] contained within an LPS is referred to as the O [[antigen]], O [[polysaccharide]], or O side-chain of the bacteria. The O antigen is attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. The structure and composition of the O chain
===Core===
{{main|Core oligosaccharide}}
The core domain always contains an oligosaccharide component that attaches directly to [[lipid A]] and commonly contains [[sugar]]s such as [[heptose]] and [[3-Deoxy-D-manno-oct-2-ulosonic acid]] (also known as KDO, keto-deoxyoctulosonate).<ref>{{
===Lipid A===
{{main|Lipid A}}
Lipid A is, in normal circumstances, a [[phosphorylated]] [[glucosamine]] [[disaccharide]] decorated with multiple [[fatty acids]]. These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane, and the rest of the LPS projects from the cell surface. The lipid A domain is the most bioactive and responsible for much of the toxicity of [[Gram-negative bacteria]]. When bacterial cells are [[lysis|lysed]] by the [[immune system]], fragments of membrane containing lipid A
==Lipooligosaccharides==
The "rough form" of LPS has a lower molecular weight due to the absence of the O polysaccharide. In its place is a short oligosaccharide: this form is known as Lipooligosaccharide (LOS), and is a glycolipid found in the outer membrane of some types of [[Gram-negative bacteria]], such as ''[[Neisseria]]'' spp. and ''[[Haemophilus]]'' spp.<ref name="
==LPS detoxification ==
A highly conserved host enzyme called [[acyloxyacyl hydrolase]] (AOAH) may detoxify LPS when it enters, or is produced in, animal tissues. It may also convert LPS in the intestine into an LPS inhibitor. Neutrophils, macrophages and dendritic cells produce this lipase, which inactivates LPS by removing the two secondary acyl chains from lipid A to produce tetraacyl LPS. If mice are given LPS parenterally, those that lack AOAH develop high titers of non-specific antibodies, develop prolonged hepatomegaly, and experience prolonged endotoxin tolerance. LPS inactivation may be required for animals to restore homeostasis after parenteral LPS exposure.<ref>{{Cite book |title=Chapter 2 Kill the
Dephosphorylation of LPS by [[Alkaline phosphatase#Intestinal alkaline phosphatase|intestinal alkaline phosphatase]] can reduce the severity of ''[[Salmonella tryphimurium]]'' and ''[[Clostridioides difficile]]'' [[Clostridioides difficile infection|infection]] restoring normal gut microbiota.<ref name="
"[[Intestinal permeability|leaky gut]]") from bacteria by dephosphorylating the Lipid A portion of LPS.<ref name="
==Biosynthesis and transport==
{{Clear}}[[File:LPS-Assembly.svg|thumb|left|380px|'''LPS final assembly:''' [[O antigen|O-antigen]] subunits are translocated across the inner membrane (by Wzx) where they are polymerized (by Wzy, chain length determined by Wzz) and ligated (by WaaL) on to complete Core-[[Lipid A]] molecules (which were translocated by MsbA).<ref name="Wang">{{Cite journal |vauthors=Wang X, Quinn PJ |year=2010 |title=Lipopolysaccharide: Biosynthetic pathway and structure modification |journal=Prog. Lipid Res. |volume=49 |issue=2 |pages=97–107 |doi=10.1016/j.plipres.2009.06.002 |pmid=19815028}}</ref>]] [[File:LPS-Transport.svg|thumb|left|380px|'''LPS transport:''' Completed LPS molecules are transported across the periplasm and outer membrane by the proteins [[LptA]], B, C, D, E, F, and G<ref name="ruiz">{{Cite journal |vauthors=Ruiz N, Kahne D, Silhavy TJ |year=2009 |title=Transport of lipopolysaccharide across the cell envelope: the long road of discovery |journal=Nat. Rev. Microbiol. |volume=7 |issue=9 |pages=677–83 |doi=10.1038/nrmicro2184 |pmc=2790178 |pmid=19633680}}</ref>]]▼
{{clear}}
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<ref>{{Cite journal |last=Romano |first=K.P. |last2=Hung |first2=D.T. |date=2023-03 |title=Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance |url=https://linkinghub.elsevier.com/retrieve/pii/S0167488922001999 |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |language=en |volume=1870 |issue=3 |pages=119407 |doi=10.1016/j.bbamcr.2022.119407 |pmc=PMC9922520 |pmid=36543281}}</ref>The entire process of making LPS starts with a molecule called lipid A-Kdo2, which is first created on the surface of a cell's inner membrane. Then, additional sugars are added to this molecule on the inner membrane before it's moved to the space between the inner and outer membranes with the help of a protein called MsbA. The O-antigen, another part of LPS, is made by special enzyme complexes on the inner membrane. It's then moved to the outer membrane through three different systems: one is Wzy-dependent, another relies on ABC transporters, and the third involves a synthase-dependent process.▼
{{clear}}
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Ultimately, LPS is transported to the outer membrane by a membrane-to-membrane bridge of lipolysaccharide transport (Lpt) proteins.<ref name="Ruiz_2009" /><ref>{{cite journal | vauthors = Sherman DJ, Xie R, Taylor RJ, George AH, Okuda S, Foster PJ, Needleman DJ, Kahne D | display-authors = 6 | title = Lipopolysaccharide is transported to the cell surface by a membrane-to-membrane protein bridge | journal = Science | volume = 359 | issue = 6377 | pages = 798–801 | date = February 2018 | pmid = 29449493 | pmc = 5858563 | doi = 10.1126/science.aar1886 | bibcode = 2018Sci...359..798S }}</ref> This transporter is a potential antibiotic target.<ref>{{cite journal | vauthors = Pahil KS, Gilman MS, Baidin V, Clairfeuille T, Mattei P, Bieniossek C, Dey F, Muri D, Baettig R, Lobritz M, Bradley K, Kruse AC, Kahne D | display-authors = 6 | title = A new antibiotic traps lipopolysaccharide in its intermembrane transporter | journal = Nature | pages = 572–577 | date = January 2024 | volume = 625 | issue = 7995 | doi = 10.1038/s41586-023-06799-7 | doi-access = free | pmid = 38172635 | pmc = 10794137 | bibcode = 2024Natur.625..572P }}</ref><ref>{{cite journal | vauthors = Zampaloni C, Mattei P, Bleicher K, Winther L, Thäte C, Bucher C, Adam JM, Alanine A, Amrein KE, Baidin V, Bieniossek C, Bissantz C, Boess F, Cantrill C, Clairfeuille T, Dey F, Di Giorgio P, du Castel P, Dylus D, Dzygiel P, Felici A, García-Alcalde F, Haldimann A, Leipner M, Leyn S, Louvel S, Misson P, Osterman A, Pahil K, Rigo S, Schäublin A, Scharf S, Schmitz P, Stoll T, Trauner A, Zoffmann S, Kahne D, Young JA, Lobritz MA, Bradley KA | display-authors = 6 | title = A novel antibiotic class targeting the lipopolysaccharide transporter | journal = Nature | pages = 566–571 | date = January 2024 | volume = 625 | issue = 7995 | pmid = 38172634 | doi = 10.1038/s41586-023-06873-0 | doi-access = free | pmc = 10794144 | bibcode = 2024Natur.625..566Z }}</ref>
==Biological effects on hosts infected with Gram-negative bacteria==
===LPS storage in the body===
The human body carries endogenous stores on LPS.<ref>{{cite journal | vauthors = Marshall JC| title = Lipopolysaccharide: an endotoxin or an exogenous hormone?| journal = Clin Infect Dis| volume = 41 | issue = S7 | pages = S470–80| date = 2005| pmid = 16237650 | doi = 10.1086/432000 }}</ref> The epithelial surfaces are colonized by a complex microbial flora (including gram-negative bacteria), which outnumber human cells by a factor of 10 to 1. Gram-negative bacterial will shed endotoxins. This host-microbial interaction is a symbiotic relationship which plays a critical role in systemic immunologic homeostasis. When this is disrupted, it can lead to disease such as endotoxemia and endotoxic septic shock.
===Immune response===
LPS acts as the prototypical endotoxin because it binds the [[CD14]]/[[TLR 4|TLR4]]/[[Lymphocyte antigen 96|MD2]] [[receptor (biochemistry)|receptor]] complex in many cell types, but especially in [[monocytes]], [[dendritic cells]], [[macrophage]]s and [[B cell]]s, which promotes the secretion of pro-[[inflammation|inflammatory]] [[cytokine]]s, [[nitric oxide]], and [[eicosanoids]].<ref>{{Cite book |
As part of the cellular [[stress response]], [[superoxide]] is one of the major [[reactive oxygen species]] induced by LPS in various cell types that express TLR ([[toll-like receptor]]).<ref>{{
LPS function has been under experimental research for several years due to its role in activating many [[transcription factor]]s. LPS also produces many types of mediators involved in [[septic shock]].
Endotoxins are in large part responsible for the dramatic clinical manifestations of infections with pathogenic Gram-negative bacteria, such as ''[[Neisseria meningitidis]]'', the pathogens that causes [[meningococcal disease]], including [[meningococcemia]], [[Waterhouse–Friderichsen syndrome]], and [[meningitis]].
Portions of the LPS from several bacterial strains have been shown to be chemically similar to human host cell surface molecules; the ability of some bacteria to present molecules on their surface which are chemically identical or similar to the surface molecules of some types of host cells is termed molecular [[mimicry]].<ref name="
LPS can be sensed directly by [[hematopoietic stem cell]]s (HSCs) through the bonding with TLR4, causing them to proliferate in reaction to a systemic infection. This response activate the TLR4-TRIF-ROS-p38 signaling within the HSCs and through a sustained TLR4 activation can cause a proliferative stress, leading to impair their competitive repopulating ability.<ref>{{
===Effect of variability on immune response===
[[File:Toll-like receptor pathways revised.jpg|thumbnail|right|300px|[[Toll-like receptor]]s of the [[innate immune system]] recognize LPS and trigger an [[immune response]].]]
O-antigens (the outer carbohydrates) are the most variable portion of the LPS molecule, imparting antigenic specificity. In contrast, lipid A is the most conserved part. However, lipid A composition also may vary (e.g., in number and nature of [[acyl]] chains even within or between genera). Some of these variations may impart antagonistic properties to these LPS. For example, diphosphoryl lipid A of ''[[Rhodobacter sphaeroides]]'' (RsDPLA) is a potent antagonist of LPS in human cells, but is an agonist in hamster and equine cells.<ref>{{cite journal | vauthors = Lohmann KL, Vandenplas ML, Barton MH, Bryant CE, Moore JN | title = The equine TLR4/MD-2 complex mediates recognition of lipopolysaccharide from
It has been speculated that conical lipid A (e.g., from ''[[Escherichia coli|E. coli]]'') is more agonistic, while less conical lipid A like that of ''Porphyromonas gingivalis'' may activate a different signal ([[TLR2]] instead of TLR4), and completely cylindrical lipid A like that of ''Rhodobacter sphaeroides'' is antagonistic to TLRs.<ref>{{
Normal human blood [[serum (blood)|serum]] contains anti-LOS antibodies that are bactericidal and patients that have infections caused by serotypically distinct strains possess anti-LOS antibodies that differ in their specificity compared with normal serum.<ref name="
In ''[[Neisseria gonorrhoeae]]'' it has been demonstrated that the antigenicity of LOS molecules can change during an infection due to the ability of these bacteria to synthesize more than one type of LOS,<ref name="
Taken together, these observations suggest that variations in bacterial surface molecules such as LOS can help the pathogen evade both the [[humoral immunity|humoral]] (antibody and complement-mediated) and the [[cell-mediated immunity|cell-mediated]] (killing by neutrophils, for example) host immune defenses.
===Non-canonical pathways of LPS recognition===
Recently, it was shown that in addition to [[TLR4]] mediated pathways, certain members of the family of the [[Transient receptor potential channel|transient receptor potential ion channels]] recognize LPS.<ref>{{
LPS is recognized by [[TRPV4]] on epithelial cells. TRPV4 activation by LPS was necessary and sufficient to induce nitric oxide production with a bactericidal effect.<ref>{{
===Endotoxin Activity Assay===
'''Pathophysiology'''▼
Because the LPS is very difficult to measure in whole blood and because most LPS is bound to proteins and complement, the Endotoxin Activity Assay (EAA™) was developed and cleared by the US FDA in 2003. EAA is a rapid in vitro chemiluminescent immunodiagnostic test. It utilizes a specific monoclonal antibody to measure the endotoxin activity in EDTA whole blood specimens. This assay uses the biological response of the neutrophils in a patient’s blood to an immunological complex of endotoxin and exogenous antibody – the chemiluminescent reaction formed creates an emission of light. The amount of chemiluminescence is proportional to the logarithmic concentration of LPS in the sample and is a measure of the endotoxin activity in the blood.<ref>{{cite journal | vauthors = Romaschin AD, Harris DM, Riberio MB, Paice J, Foster DM, Walker PM, Marshall JC | title = A rapid assay of endotoxin in whole blood using autologous neutrophil dependent chemiluminescence | journal = J Immunol Methods| volume = 212 | issue = 2 | pages = 169–185| date = 1998| pmid = 9672205 | doi = 10.1016/s0022-1759(98)00003-9}}</ref> The assay reacts specifically with the Lipid A moiety of LPS of Gram-negative bacteria and does not cross-react with cell wall constituents of Gram-positive bacteria and other microorganisms.
'<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>''Recent research indicates that even small LPS exposure is associated with autoimmune diseases and allergies. High levels of LPS in the blood can lead to metabolic syndrome, increasing the risk of conditions like diabetes, heart disease, and liver problems.'''▼
LPS is a powerful toxin that, when in the body, triggers inflammation by binding to cell receptors. Excessive LPS in the blood, endotoxemia, may cause a highly lethal form of sepsis known as endotoxic septic shock.<ref name="The role of endotoxin in septic sho"/> This condition includes symptoms that fall along a continuum of pathophysiologic states, starting with a systemic inflammatory response syndrome (SIRS) and ending in multiorgan dysfunction syndrome (MODS) before death. Early symptoms include rapid heart rate, quick breathing, temperature changes, and blood clotting issues, resulting in blood vessels widening and reduced blood volume, leading to cellular dysfunction.<ref name="Page_2022" />
'<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>''LPS also plays a crucial role in symptoms caused by infections from harmful bacteria, including severe conditions like Waterhouse-Friderichsen syndrome, meningococcemia, and meningitis. Certain bacteria can adapt their LPS to cause long-lasting infections in the respiratory and digestive systems.''' ▼
▲
''<ref>Page, M. J., Kell, D. B., & Pretorius, E. (2022). The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic stress (Thousand Oaks, Calif.), 6, 24705470221076390. https://doi.org/10.1177/24705470221076390</ref>'Recent studies have shown that LPS disrupts cell membrane lipids, affecting cholesterol and metabolism, potentially leading to high cholesterol, abnormal blood lipid levels, and non-alcoholic fatty liver disease. In some cases, LPS can interfere with toxin clearance, which may be linked to neurological issues.'''▼
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==Health effects==
In general the health effects of LPS are due to its abilities as a potent activator and modulator of the immune system, especially its inducement of inflammation. LPS is directly cytoxic and is highly immunostimulatory – as host immune cells recognize LPS, complement are strongly activated. Complement activation and a rising anti-inflammatory response can lead to immune cell dysfunction, immunosuppression, widespread coagulopathy, serious tissue damage and can progress to multi-system organ failure and death.<ref name="Sepsis and the evolution of human i"/>
===Endotoxemia===
The presence of endotoxins in the blood is called endotoxemia. High level of endotoxemia can lead to [[septic shock]],<ref name="
Moreover, endotoxemia of intestinal origin, especially, at the [[host-pathogen interface]], is considered to be an important factor in the development of alcoholic hepatitis,<ref>{{
[[Lipid A]] may cause uncontrolled activation of mammalian immune systems with production of [[inflammation|inflammatory]] mediators that may lead to endotoxic [[septic shock]].<ref name="
It has also been reported that [[Neisseria gonorrhoeae|gonococcal]] LOS can cause damage to human [[fallopian tube]]s.<ref name="
===Treatment of Endotoxemia===
Toraymyxin is a widely used extracorporeal endotoxin removal therapy through direct hemoadsorption (also referred to as hemoperfusion). It is a polystyrene-derived cartridge with molecules of polymyxin B (PMX-B) covalently bound to mesh fibers contained within it. Polymyxins are cyclic cationic polypeptide antibiotics derived from Bacillus polymyxa with an effective antimicrobial activity against Gram-negative bacteria, but their intravenous clinical use has been limited due to their nephrotoxicity and neurotoxicity side effects.<ref>{{cite journal | vauthors = Li J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner CR, Paterson DL | title = Colistin: The Re-Emerging Antibiotic for Multidrug-Resistant Gram-Negative Bacterial Infections.| journal = Lancet Infect Dis| volume = 6 | pages = 589–601| date = 2006| issue = 9| doi = 10.1016/S1473-3099(06)70580-1| pmid = 16931410}}</ref> The extracorporeal use of the Toraymyxin cartridge allows PMX-B to bind lipid A with a very stable interaction with its hydrophobic residues thereby neutralizing endotoxins as the blood is filtered through the extracorporeal circuit inside the cartridge, thus reversing endotoxemia and avoiding its toxic systemic effects.<ref>{{cite journal | vauthors = Virzi GM, Mattiotti M, de Cal M, Ronco C, Zanella M, DeRosa S| title = Endotoxin in Sepsis: Methods for LPS Detection and the Use of Omics Techniques| journal = Diagnostics| volume = 13 | issue = 1 | pages = 79 | date = 2022| pmid = 36611371 | doi = 10.3390/diagnostics13010079| doi-access = free| pmc = 9818564}}</ref>
===Auto-immune disease===
The [[molecular mimicry]] of some LOS molecules is thought to cause autoimmune-based host responses, such as flareups of [[multiple sclerosis]].<ref name="
===Link to obesity===
Epidemiological studies have shown that increased endotoxin load, which can be a result of increased populations of endotoxin-producing bacteria in the intestinal tract, is associated with certain obesity-related patient groups.<ref name="
=== Depression ===
There is experimental and observational evidence that LPS might play a role in depression. Administration of LPS in mice can lead to depressive symptoms, and there seem to be elevated levels of LPS in some people with depression. Inflammation may sometimes play a role in the development of depression, and LPS is pro-inflammatory.<ref name="
===Cellular senescence===
Inflammation induced by LPS can induce [[cellular senescence]], as has been shown for the lung [[Epithelium|epithelial cells]] and [[Microglia|microglial cells]] (the latter leading to [[neurodegeneration]]).<ref name="
==Role as contaminant in biotechnology and research ==
Lipopolysaccharides are frequent contaminants in [[plasmid]] [[DNA]] prepared from bacteria or proteins expressed from bacteria, and ''must'' be removed from the DNA or protein to avoid contaminating experiments and to avoid toxicity of products manufactured using [[industrial fermentation]].<ref>{{
[[Ovalbumin]] is frequently contaminated with endotoxins. Ovalbumin is one of the extensively studied proteins in animal models and also an established model allergen for airway hyper-responsiveness (AHR). Commercially available ovalbumin that is contaminated with LPS can falsify research results, as it does not accurately reflect the effect of the protein antigen on animal physiology.<ref>{{Cite journal |last1=Watanabe |first1=Junji |last2=Miyazaki |first2=Yasunari |last3=Zimmerman |first3=Guy A. |last4=Albertine |first4=Kurt H. |last5=McIntyre |first5=Thomas M. |date=24 October 2003 |title=Endotoxin contamination of ovalbumin suppresses murine immunologic responses and development of airway hyper-reactivity |journal=The Journal of Biological Chemistry |volume=278 |issue=43 |pages=42361–42368 |doi=10.1074/jbc.M307752200 |issn=0021-9258 |pmid=12909619 |doi-access=free}}</ref>▼
In pharmaceutical production, it is necessary to remove all traces of endotoxin from drug product containers, as even small amounts of endotoxin will cause illness in humans. A [[depyrogenation]] oven is used for this purpose. Temperatures in excess of 300 °C are required to fully break down LPS.<ref>{{Cite web |last=16 December 2014 |title=The Detection of Endotoxins Via the LAL Test, the Chromogenic Method |url=http://www.wakopyrostar.com/blog/post/the-detection-of-endotoxins-via-the-lal-test-the-chromogenic-method/ |url-status=dead |archive-url=https://web.archive.org/web/20150329083636/http://www.wakopyrostar.com/blog/post/the-detection-of-endotoxins-via-the-lal-test-the-chromogenic-method |archive-date=29 March 2015 |access-date=14 March 2015}}</ref>▼
The standard [[assay]] for detecting presence of endotoxin is the [[Limulus Amebocyte Lysate]] (LAL) assay, utilizing blood from the [[Horseshoe crab]] (''Limulus polyphemus'').<ref name="pmid24019589">{{Cite journal |vauthors=Iwanaga S |year=2007 |title=Biochemical principle of Limulus test for detecting bacterial endotoxins |journal=Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. |volume=83 |issue=4 |pages=110–9 |bibcode=2007PJAB...83..110I |doi=10.2183/pjab.83.110 |pmc=3756735 |pmid=24019589}}</ref> Very low levels of LPS can cause coagulation of the limulus lysate due to a powerful amplification through an enzymatic cascade. However, due to the dwindling population of horseshoe crabs, and the fact that there are factors that interfere with the LAL assay, efforts have been made to develop alternative assays, with the most promising ones being [[ELISA]] tests using a [[recombinant protein|recombinant]] version of a protein in the LAL assay, Factor C.<ref name="pmid11451451">{{Cite journal |vauthors=Ding JL, Ho B |year=2001 |title=A new era in pyrogen testing |url=http://www.horseshoecrab.org/research/sites/default/files/TIBTECH-rFC.pdf |url-status=dead |journal=Trends Biotechnol. |volume=19 |issue=8 |pages=277–81 |doi=10.1016/s0167-7799(01)01694-8 |pmid=11451451 |archive-url=https://web.archive.org/web/20140102191953/http://www.horseshoecrab.org/research/sites/default/files/TIBTECH-rFC.pdf |archive-date=2 January 2014 |access-date=2 January 2014}}</ref>▼
▲[[Ovalbumin]] is frequently contaminated with endotoxins. Ovalbumin is one of the extensively studied proteins in animal models and also an established model allergen for airway hyper-responsiveness (AHR). Commercially available ovalbumin that is contaminated with LPS can falsify research results, as it does not accurately reflect the effect of the protein antigen on animal physiology.<ref>{{
▲In pharmaceutical production, it is necessary to remove all traces of endotoxin from drug product containers, as even small amounts of endotoxin will cause illness in humans. A [[depyrogenation]] oven is used for this purpose. Temperatures in excess of 300 °C are required to fully break down LPS.<ref>{{Cite web |
▲The standard [[assay]] for detecting presence of endotoxin is the [[Limulus Amebocyte Lysate]] (LAL) assay, utilizing blood from the [[Horseshoe crab]] (''Limulus polyphemus'').<ref name="
== See also ==
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