Eicosanoid 631312 225666739 2008-07-14T20:27:29Z Rjwilmsi 203434 gen fixes + link/fix date fields in cite templates (explanation [[User:Rjwilmsi#My_correction_of_dates_in_templates|here]]) using [[Project:AutoWikiBrowser|AWB]] {{Mergefrom|Eicosanoid biosynthesis|date=March 2008}} [[Image:Eicosanoid synthesis.svg|right|thumb|400px|Pathways in biosynthesis of '''eicosanoid'''s from arachidonic acid: there are parallel paths from [[Eicosapentaenoic acid|EPA]] & [[Dihomo-gamma-linolenic acid|DGLA]].]] In biochemistry, '''eicosanoids''' are [[lipid signaling|signaling molecules]] made by [[oxygenation]] of twenty-carbon [[essential fatty acid]]s, (EFAs). They exert complex control over many bodily systems, mainly in [[inflammation]] or [[Immune system|immunity]], and as messengers in the [[central nervous system]]. The networks of controls that depend upon eicosanoids are among the most complex in the human body. Eicosanoids derive from either [[Omega-3 fatty acid|omega-3]] (ω-3) or [[Omega-3 fatty acid|omega-6]] (ω-6) EFAs. The ω-6 eicosanoids are generally pro-inflammatory; ω-3's are much less so. The amounts and balance of these fats in a person's diet will affect the body's eicosanoid-controlled functions, with effects on [[cardiovascular disease]], [[triglycerides]], [[blood pressure]], and [[arthritis]]. Anti-inflammatory drugs such as [[aspirin]] and other [[NSAID]]s act by downregulating eicosanoid synthesis. There are four families of eicosanoids&mdash;the [[prostaglandin]]s, [[prostacyclin]]s, the [[thromboxane]]s and the [[leukotriene]]s. For each, there are two or three separate series, derived either from an ω-3 or ω-6 EFA. These series' different activities largely explain the health effects of ω-3 and ω-6 fats.<ref name=DeCaterina>{{cite journal | author=DeCaterina, R and Basta, G | journal= European Heart Journal Supplements | volume =3, Suppl D | pages=D42–D49 | title= n-3 Fatty acids and the inflammatory response &ndash; biological background | url = http://eurheartjsupp.oxfordjournals.org/cgi/reprint/3/suppl_D/D42.pdf | accessdate= 2006-02-10 |year=June, 2001|format=PDF}}</ref><ref name=Funk>{{cite journal | author=Funk, Colin D. | journal=Science |date=[[30 November]] [[2001]] | volume= 294| issue= 5548 |pages= 1871–1875 |doi = 10.1126/science.294.5548.1871 | title= Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology | accessdate = 2007-01-08 | url= http://www.sciencemag.org/cgi/content/full/294/5548/1871 | pmid= 11729303}}</ref><ref name=Piomelli>{{cite journal|author=Piomelli, Daniele |title=Arachidonic Acid |url= http://www.acnp.org/g4/GN401000059/Default.htm | year= 2000|accessdate=2006-03-03|work=Neuropsychopharmacology: The Fifth Generation of Progress}}</ref><ref name=Soberman>{{cite journal | author=Soberman, Roy J. and Christmas, Peter | title =The organization and consequences of eicosanoid signaling | journal =J. Clin. Invest| volume= 111 |pages=1107–1113 |year=2003 | url = http://www.jci.org/cgi/content/full/111/8/1107 | doi = 10.1172/JCI200318338 | accessdate = 2007-01-05}}</ref> ==Nomenclature== :''See related detail at [[Essential fatty acid interactions#Eicosanoid series nomenclature|Essential Fatty Acid Interactions&mdash;Nomenclature]]'' "Eicosanoid" (''eicosa-'', [[Greek language|Greek]] for "twenty"; ''see [[icosahedron]]'') is the collective term<ref name=Beare>{{cite web | author=Beare-Rogers | title=IUPAC Lexicon of Lipid Nutrition | year=2001 | url=http://www.iupac.org/publications/pac/2001/pdf/7304x0685.pdf |accessmonthday=June 1 |accessyear=2006|format=PDF}}</ref> for oxygenated derivatives of three different 20-carbon [[essential fatty acids]]: *[[Eicosapentaenoic acid]] ('''EPA'''), an ω-3 fatty acid with 5 [[double bond]]s; *[[Arachidonic acid]] ('''AA'''), an ω-6 fatty acid, with 4 double bonds; *[[Dihomo-gamma-linolenic acid]] ('''DGLA'''), an ω-6, with 3 double bonds. Current usage limits the term to the [[leukotriene]]s ('''LT''') and three types of [[prostanoid]]s&mdash;[[prostaglandin]]s ('''PG''') [[prostacyclin]]s ('''PGI'''), and [[thromboxane]]s ('''TX'''). This is the definition used in this article. However, several other classes can technically be termed eicosanoid, including the [[hepoxilin]]s, [[resolvins]], [[isofuran]]s, [[isoprostane]]s, [[lipoxin]]s, [[epi-lipoxin]]s, [[epoxyeicosatrienoic acid]]s (EETs) and [[Cannabinoid#Endogenous Cannabinoids|endocannabinoids]]. LTs and prostanoids are sometimes termed 'classic eicosanoids'<ref name=vandyke>{{cite journal |author=Van Dyke TE, Serhan CN |title=Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases |journal=J. Dent. Res. | volume=82 |issue=2 |pages=82–90 |year=2003 |pmid=12562878 |doi=|accessdate=2007-10-28 }}</ref><ref name=Serhan> {{cite journal |author=Serhan CN, Gotlinger K, Hong S, Arita M |title=Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis |journal=Prostaglandins Other Lipid Mediat. |volume=73 |issue=3-4 |pages=155–72 |year=2004 |pmid=15290791 |doi=|accessdate=2007-10-28}}</ref><ref name=Anderle>{{ cite journal |author=Anderle P, Farmer P, Berger A, Roberts MA |title=Nutrigenomic approach to understanding the mechanisms by which dietary long-chain fatty acids induce gene signals and control mechanisms involved in carcinogenesis |journal=Nutrition (Burbank, Los Angeles County, Calif.) |volume=20 |issue=1 |pages=103–8 |year=2004 |pmid=14698023 | doi=|accessdate=2007-10-28 }}</ref> in contrast to the 'novel', 'eicosanoid-like' or '[[nonclassic eicosanoid]]s'.<ref name=Evans>{{ cite journal |author=Evans AR, Junger H, Southall MD, ''et al'' |title=Isoprostanes, novel eicosanoids that produce nociception and sensitize rat sensory neurons |journal=J. Pharmacol. Exp. Ther. |volume=293 |issue=3 |pages=912–20 |year=2000 |pmid=10869392 |doi=|accessdate=2007-10-28}}</ref><ref name=O'Brien>{{cite journal |author=O'Brien WF, Krammer J, O'Leary TD, Mastrogiannis DS |title=The effect of acetaminophen on prostacyclin production in pregnant women |journal=Am. J. Obstet. Gynecol. |volume=168 |issue=4 |pages=1164–9 |year=1993 |pmid=8475962 |doi=}}</ref><ref name="pmid11306946">{{cite journal |author=Behrendt H, Kasche A, Ebner von Eschenbach C, Risse U, Huss-Marp J, Ring J |title=Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergic sensitization |journal=Int. Arch. Allergy Immunol. |volume=124 |issue=1-3 |pages=121–5 |year=2001 |pmid=11306946 |doi=10.1159/000053688|accessdate=2007-11-02}}</ref><ref name="pmid10477044">{{cite journal |author=Sarau HM, Foley JJ, Schmidt DB, ''et al'' |title=In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity |journal=Prostaglandins Leukot. Essent. Fatty Acids |volume=61 |issue=1 |pages=55–64 |year=1999 |pmid=10477044 |doi=10.1054/plef.1999.0074|accessdate=2007-11-02}}</ref> A particular eicosanoid is denoted by a four-character abbreviation, composed of: * Its two letter abbreviation (above),<ref>Prostacyclin&mdash;PGI&mdash;was previously classified as prostaglandin and retains its old identifier.</ref> *One A-B-C sequence-letter;<ref name=CyberlipidP> Eicosanoids with different letters have placement of double-bonds and different [[functional group]]s attached to the molecular skeleton. Letters indicate roughly the order the eicosanoids were first described in the literature. For diagrams for PG &#91;A&ndash;H&#93; see {{cite web| url= http://www.cyberlipid.org/prost1/pros0001.htm |author=Cyberlipid Center|title = Prostanoids|accessdate=2007-02-05}} </ref> and *A subscript, indicating the number of [[Covalent bond|double bonds]]. Examples are: * The EPA-derived prostanoids have three double bonds, (e.g. PGG<sub>3</sub>, PGH<sub>3</sub>, PGI<sub>3</sub>, TXA<sub>3</sub>) while its leukotrienes have five, (LTB<sub>5</sub>). *The AA-derived prostanoids have two double bonds, (e.g. PGG<sub>2</sub>, PGH<sub>2</sub>, PGI<sub>2</sub>, TXA<sub>2</sub>) while its leukotrienes have four, (LTB<sub>4</sub>). Furthermore, [[stereochemistry]] may differ among the pathways, indicated by Greek letters, e.g. for (PGF<sub>2α</sub>). ==Biosynthesis== {{Main|Eicosanoid biosynthesis}} Two families of [[enzymes]] catalyze fatty acid oxygenation to produce the eicosanoids: * [[Cyclooxygenase]], or COX, generates the prostanoids. * [[Lipoxygenase]], in several forms. 5-lipoxygenase (5-LO) generates the leukotrienes. Eicosanoids are not stored within cells, but are [[Biosynthesis|synthesized]] as required. They derive from the fatty acids that make up the [[cell membrane]] and [[Nuclear envelope|nuclear membrane]]. Eicosanoid biosynthesis begins when cell is activated by mechanical trauma, [[cytokines]], [[growth factor]]s or other stimuli. (The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.) [[Phospholipase]] is released at the [[cell membrane]] and travels to the [[nuclear membrane]]. There, it frees 20-carbon [[essential fatty acid]]s. This event appears to be the [[rate-determining step]] for eicosanoid formation. Next, the free fatty acid is oxygenated along any of several pathways; see the [[Eicosanoid biosynthesis|''Pathways'' table]]. The classical pathways add [[Oxygen|molecular oxygen]] (O<sub>2</sub>) ''via'' [[lipoxygenase]] or [[Cyclooxygenase|COX]]. Although the fatty acid is [[Symmetry|symmetric]], the resulting eicosanoids are [[Chirality (chemistry)|chiral]]; the oxidation proceeds with high [[stereospecificity]]. ===Peroxidation and reactive oxygen species=== The generation of eicosanoids is hazardous to the cell, particularly as it occurs close to the nucleus. Oxidation releases [[reactive oxygen species]] (ROS). Further, the initial products in eicosanoid generation are themselves highly reactive [[peroxide]]s. E.g., LTA<sub>4</sub> can form [[adduct]]s with tissue [[DNA]]. Lipoxygenase can generate cellular damage; [[Murinae|murine]] models implicate 15-lipoxygenase in the [[pathogenesis]] of [[atherosclerosis]].<ref name=Cyrus>{{cite journal | author=Cyrus, Tillmann | journal= J Clin Invest | url= http://www.jci.org/cgi/content/abstract/103/11/1597 | year= June 1999 |volume = 103| number =11| pages= 1597–1604n | title=Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice | doi=10.1172/JCI5897}}</ref><ref name=Schewe>{{cite journal | author=Schewe T. |journal= Biol Chem. |year= 2002 Mar-Apr| volume= 383|issue= 3-4 | title = 15-lipoxygenase-1: a prooxidant enzyme | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12033428 | accessdate= 2007-01-09 | unused_data=|pages: 365-74}}</ref> Nevertheless, there is an advantage in the proximity to the nucleus, since, PGs and LTs may signal or regulate [[Transcription (genetics)|DNA-transcription]] there; For instance, LTB<sub>4</sub> is a [[ligand]] for [[Peroxisome proliferator-activated receptor|PPAR&alpha;]],<ref name=Funk /> ''(see diagram at [[Peroxisome proliferator-activated receptor| PPAR]]).'' There are elaborate mechanisms to prevent unwanted oxidation. COX, the lipoxygenases and the phospholipases are tightly controlled&mdash;there are at least eight proteins activated to coordinate generation of leukotrienes. Several of these exist in multiple [[isoforms]].<ref name=Soberman/> Perhaps eicosanoid signaling evolved from the detoxification of ROS. Several of enzymes which are biosynthetic for eicosanoids belong to families whose functions are largely involved with cellular detoxification. {| border=0 width=550 align="center" style="border-top:1px solid black; border-right:1px solid black; border-bottom:1px solid black; border-left:1px solid black;" |+'''Structures of Selected Eicosanoids''' |- | align="center"|[[Image:Prostaglandin E1.svg|200px]] | colspan="2" align="center"| [[Image:Thromboxane A2 acsv.svg|170px]]<!--18Oct07: narrowed 2nd/3rd images from 200px--> | align="center"| [[Image:Leukotriene B4.svg|180px|]] |- | align="center" | Prostaglandin E<sub>1</sub>. The 5-member ring is characteristic of the class. | colspan="2" align="center"| Thromboxane A<sub>2</sub>. Oxygens<br/>have moved into the ring. | align="center"| Leukotriene B<sub>4</sub>. Note the 3 conjugated double bonds. |- | colspan="2" align="center"| [[Image:Prostaglandin I2.png|200px]] | colspan="2" align="center"|[[Image:Leukotriene E4.svg|200px]] |- | colspan="2" align="center"| Prostacyclin I<sub>2</sub>. The second ring distinguishes it from the prostaglandins. | colspan="2" align="center"|Leukotriene E<sub>4</sub>, an example of a cysteinyl leukotriene. |} ===Prostanoid pathways=== {{Main|Prostanoid#biosynthesis}} :''Several drugs lower inflammation by blocking prostanoid synthesis; see detail at [[Cyclooxygenase]], [[Aspirin]] and [[Non-steroidal anti-inflammatory drug|NSAID]].'' <!--Left to do in this section cox-1 and -2 invoked by different stimulii competition for COX by n-3, -6 discovery of synthetic pathways control of which prostanoid path after PGH discussion of different stimuli and the resulting different products control of removal, disactivation sites of synthesis in the human body use of inactive end-products to monitor short-lived prostanoids --> [[Cyclooxygenase]] (''COX'') comes in at least three [[isoform]]s, ''COX-1, -2, -3''.<ref name=Warner>{{cite journal | author=Warner, Timothy D. and Mitchell, Jane A. | title= Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum? | url=http://www.pnas.org/cgi/content/extract/99/21/13371 | year = October 8, 2002 | doi= 10.1073/pnas.222543099 | journal =PNAS | volume= 99 | issue=21 | pages=13371–13373 | accessdate = 2007-01-05 | pmid= 12374850}}</ref> COX-1 is responsible for basal prostaglandin synthesis, while COX-2 is important in inflammatory and "induced" settings.<ref name=Funk/> COX-3 is active in nervous tissue.<ref name=Piomelli/> COX catalyzes the conversion of the free essential fatty acids to prostanoids by a two-step process. First, two molecules of O<sub>2</sub> are added as two peroxide linkages, and a 5-member carbon ring is forged near the middle of the fatty acid chain. This forms the short-lived, unstable intermediate Prostaglandin G (PGG). Next, one of the peroxide linkages sheds a single oxygen, forming PGH. ''(See diagrams and more detail of these steps at [[Cyclooxygenase]]).'' All three classes of prostanoids originate from PGH. All have distinctive rings in the center of the molecule. They differ in their structures. The PGH compounds (parents to all the rest) have a 5-carbon ring, bridged by two oxygens (a peroxide.) As the example in ''Structures of Selected Eicosanoids'' figure shows, the derived prostaglandins contain a single, unsaturated 5-carbon ring. In prostacyclins, this ring is conjoined to another oxygen-containing ring. In thromboxanes the ring becomes a 6-member ring with one oxygen. The leukotrienes do not have rings. === Leukotriene pathways === {{Main|Leukotriene#synthesis}} <!-- To do for this section cut much of the chemical detail signals which initiate lk synthesis n-3/n-6 competition lipoxygenase inhibitors sites in the body where lks are synthesized overall control of lk production --> The enzyme 5-[[lipoxygenase]] (5-LO) uses 5-lipoxygenase activating protein (FLAP) to convert [[arachidonic acid]] into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously [[redox|reduces]] to 5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into [[leukotriene]] A<sub>4</sub> (LTA<sub>4</sub>), which may be converted into LTB<sub>4</sub> by the enzyme leukotriene A4 epoxide hydrolase. [[Eosinophil]]s, [[mast cell]]s, and [[alveoli|alveolar]] [[macrophage]]s use the enzyme leukotriene C4 synthase to conjugate [[glutathione]] with LTA<sub>4</sub> to make LTC<sub>4</sub>, which is transported outside the cell, where a [[glutamic acid]] [[moiety]] is removed from it to make LTD<sub>4</sub>. The leukotriene LTD<sub>4</sub> is then cleaved by dipeptidases to make LTE<sub>4</sub>. The leukotrienes LTC<sub>4</sub>, LTD<sub>4</sub> and LTE<sub>4</sub> all contain [[cysteine]] and are collectively known as the cysteinyl leukotrienes. ==Function and pharmacology== <center> {| class=wikitable |+ Metabolic actions of selected prostanoids and leukotrienes<sup>†</sup><ref name=University >{{cite web | author=University of Kansas Medical Center | year = 2004 | title = Eicosanoids and Inflammation | url = http://classes.kumc.edu/som/bioc801/small_group/eicosanoids/eicosanoids-2004.pdf | accessdate = 2007-01-05|format=PDF}}</ref> |- | PGD<sub>2</sub> |Promotion of sleep | TXA<sub>2</sub> | Stimulation of platelet<br>aggregation; vasoconstriction |- |PGE<sub>2</sub> | Smooth muscle contraction; <br>inducing pain, heat, fever; <br>[[bronchoconstriction]] |15d-PGJ<sub>2</sub> |[[Adipocyte]] differentiation |- |PGF<sub>2α</sub> |[[Contraction (childbirth)|Uterine contraction]] |LTB<sub>4</sub> | Leukocyte [[chemotaxis]] |- |PGI<sub>2</sub> |Inhibition of platelet aggregation; <br>vasodilation; [[Prenatal development#Fertilization and embryogenesis|embryo implantation]] | Cysteinyl-LTs | Anaphylaxis; bronchial smooth<br>muscle contraction. |- |colspan=4 align=center|<small><sup>†</sup>Shown eicosanoids are AA-derived; EPA-derived generally have weaker activity</small> |- |} </center> Eicosanoids exert complex control over many bodily systems, mainly in [[inflammation]] or [[Immune system|immunity]], and as messengers in the [[central nervous system]]. They are found in most living things. In humans, eicosanoids are local [[hormone]]s that are released by most cells, act on that same cell or nearby cells (i.e., they are [[autocrine]] and [[paracrine]] mediators), and then are rapidly inactivated. Eicosanoids have a short [[Elimination half-life|half-life]], ranging from seconds to minutes. Dietary antioxidants inhibit the generation of some inflammatory eicosanoids, e.g. [[Resveratrol|trans-resveratrol]] against thromboxane and some leukotrienes.<ref name=Pace>{{cite journal | author=Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. | journal = Clin Chim Acta. |year=1995 March 31| volume= 235 |issue=2|pages=207–19 | title = The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease | accessdate= 2007-01-10 | pmid=7554275 | doi = 10.1016/0009-8981(95)06045-1}}</ref> Most eicosanoid receptors are members of the [[G protein-coupled receptor]] superfamily; see the ''Receptors'' table or the article [[eicosanoid receptor]]s. {| class="wikitable" style="margin: 1em 0 1em 1em; float: right;" |+Receptors: There are specific receptors for all eicosanoids (see also: [[eicosanoid receptor]]s) |Leukotrienes: * CysLT1 (Cysteinyl leukotriene<br> receptor type 1) * CysLT2 (Cysteinyl leukotriene <br>receptor type 2) * BLT1 (Leukotriene B4 receptor) |- |Prostanoids: * PGD<sub>2</sub>: DP-(PGD<sub>2</sub>) * PGE<sub>2</sub>: ** EP<sub>1</sub>-(PGE<sub>2</sub>) ** EP<sub>2</sub>-(PGE<sub>2</sub>) ** EP<sub>3</sub>-(PGE<sub>2</sub>) ** EP<sub>4</sub>-(PGE<sub>2</sub>) * PGF<sub>2α</sub>: FP-(PGF<sub>2α</sub>) * PGI<sub>2</sub> (prostacyclin): IP-(PGI<sub>2</sub>) * TXA<sub>2</sub> (thromboxane): TP-(TXA<sub>2</sub>) |} === The &omega;-3 and &omega;-6 series === {{main|Essential fatty acid interactions}} {{Cquote|The reduction in AA-derived eicosanoids and the diminished activity of the alternative products generated from ω-3 fatty acids serve as the foundation for explaining some of the beneficial effects of greater ω-3 intake.|40px|40px|Kevin Fritsche|Fatty Acids as Modulators of the Immune Response<ref name=Fritsche>{{cite journal | author=Fritsche, Kevin | journal= Annual Review of Nutrition | volume= 26 |pages=45–73 |year= August 2006 | doi= 10.1146/annurev.nutr.25.050304.092610 | title= Fatty Acids as Modulators of the Immune Response | url= http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.nutr.25.050304.092610?journalCode=nutr | accessdate= 2007-01-11}}</ref>}} [[Arachidonic acid]] (AA; 20:4 ω-6) sits at the head of the 'arachidonic acid cascade'&mdash;more than twenty different eicosanoid-mediated [[signals (biology)|signaling paths]] controlling a wide array of cellular functions, especially those regulating [[inflammation]], immunity and the [[central nervous system]].<ref name=Piomelli/> In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. [[Eicosapentaenoic acid|EPA (20:5 &omega;-3)]] provides the most important competing cascade. [[Dihomo-gamma-linolenic acid|DGLA (20:3 &omega;-6)]] provides a third, less prominent cascade. These two parallel cascades soften the inflammatory effects of AA and its products. Low dietary intake of these less-inflammatory essential fatty acids, especially the ω-3s, has been linked to several inflammation-related diseases, and perhaps some [[mental illness]]es. The U.S. [[National Institutes of Health]] and the [[National Library of Medicine]] state that there is 'A' level evidence ('strong scientific evidence') that increased dietary ω-3 improves outcomes in [[hypertriglyceridemia]], secondary [[cardiovascular disease]] prevention and [[hypertension]]. There is 'B' level evidence ('good scientific evidence') for increased dietary ω-3 in [[Prevention (medical)|primary prevention]] of cardiovascular disease, [[rheumatoid arthritis]] and protection from [[Ciclosporin|ciclosporin toxicity]] in [[organ transplant]] patients. They also note more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders.<ref name=National>{{cite web | author=National Institute of Health | url= http://www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-fishoil.html | title=Omega-3 fatty acids, fish oil, alpha-linolenic acid |accessmonthday=March 26 | accessyear=2006| date= 2005-08-01}}</ref> Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They (a) alter [[membrane fluidity|membrane composition and function]], including the composition of [[lipid raft]]s; (b) change [[cytokine]] biosynthesis and (c) directly activate gene transcription.<ref name=Fritsche /> Of these, the action on eicosanoids is the best explored. <br style="clear:both;"/> ====Mechanisms of &omega;-3 action==== [[Image:EFA to Eicosanoids.svg|440px|thumb|right|EFA sources: Essential fatty acid production and metabolism to form eicosanoids. At each step, the &omega;-3 and &omega;-6 cascades compete for the enzymes.]] The eicosanoids from AA generally promote inflammation. Those from EPA and from [[Gamma-linolenic acid|GLA]] (''via'' DGLA) are generally less inflammatory, or inactive, or even anti-inflammatory. The figure shows the ω-3 and -6 synthesis chains, along with the major eicosanoids from AA, EPA and DGLA. Dietary ω-3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways, along the eicosanoid pathways: *''Displacement''&mdash;Dietary ω-3 decreases tissue concentrations of AA, so there is less to form ω-6 eicosanoids. *''Competitive inhibition''&mdash;DGLA and EPA compete with AA for access to the cyclooxygenase and lipoxygenase enzymes. So the presence of DGLA and EPA in tissues lowers the output of AA's eicosanoids. *''Counteraction''&mdash;Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts. ===Role in inflammation === [[Aulus Cornelius Celsus|Since antiquity]], the cardinal signs of inflammation have been known as: calor (warmth), dolor (pain), tumor (swelling) and rubor (redness). The eicosanoids are involved with each of these signs. {| class="wikitable" style="margin: 1em 0 1em 1em; float: right;" |+Pharmacy: Eicosanoid, eicosanoid analogs and receptor agonists/antagonists used as medicines |- ! Medicine ! Type ! Medical condition or use |- | valign=top |[[Alprostadil]] | valign=top |PGI<sub>1</sub> | [[Erectile dysfunction]], maintaining a <br> [[patent ductus arteriosus]] in the [[fetus]] |- | valign=top |[[Beraprost]] | valign=top |PGI<sub>1</sub> analog | [[Pulmonary hypertension]], avoiding<br> [[reperfusion injury]] |- |[[Bimatoprost]] | PG analog | [[Glaucoma]], ocular [[hypertension]] |- | valign=top |[[Carboprost]] | valign=top |PG analog | [[Induction (birth)|Labor induction]], [[abortifacient]]<br> in early pregnancy |- | [[Dinoprostone]] | PGE<sub>2</sub> | [[Induction (birth)|Labor induction]] |- | [[Iloprost]] | PGI<sub>2</sub> analog | [[Pulmonary hypertension|Pulmonary arterial hypertension]] |- | [[Latanoprost]] | PG analog | [[Glaucoma]], ocular [[hypertension]] |- | valign=top |[[Misoprostol]] | valign=top |PGE<sub>1</sub> analog | [[Peptic ulcer|Stomach ulcers]], [[Induction (birth)|labor induction]], <br>[[abortifacient]] |- | valign=top |[[Montelukast]] | LT [[receptor antagonist|receptor <br>antagonist]] | valign=top |[[Asthma]], seasonal [[allergy|allergies]] |- | [[Travoprost]] | PG analog | [[Glaucoma]], ocular [[hypertension]] |- | [[Treprostinil]] | PGI analog | [[Pulmonary hypertension]] |- | valign=top |U46619 | Longer lived <br>TX analog | valign=top |Research only |- | valign=top |[[Zafirlukast]] | LT [[receptor antagonist|receptor <br>antagonist]] | valign=top |[[Asthma]] |- |} ''[[Erythema|Redness]]''&mdash;An insect's sting will trigger the classic inflammatory response. Short acting [[vasoconstrictor]]s &mdash; TXA<sub>2</sub>&mdash;are released quickly after the injury. The site may momentarily turn pale. Then TXA<sub>2</sub> mediates the release of the [[vasodilators]] PGE<sub>2</sub> and LTB<sub>4</sub>. The blood vessels engorge and the injury reddens.<br> ''[[Edema|Swelling]]''&mdash;LTB<sub>4</sub> makes the blood vessels more permeable. Plasma leaks out into the connective tissues, and they swell. The process also looses pro-inflammatory cytokines.<br> ''[[Hyperalgesia|Pain]]''&mdash;The cytokines increase COX-2 activity. This elevates levels of PGE<sub>2</sub>, sensitizing pain neurons.<br> ''[[Fever|Heat]]''&mdash;PGE<sub>2</sub> is also a potent pyretic agent. Aspirin and NSAIDS&mdash;drugs that block the COX pathways and stop prostanoid synthesis&mdash;limit fever or the heat of localized inflammation. ===Action of prostanoids=== :''Main articles: [[Prostaglandin]], [[Prostacyclin]] and [[Thromboxane]]'' Prostanoids mediate local symptoms of [[inflammation]]: [[vasoconstriction]] or [[vasodilation]], [[coagulation]], [[pain]] and [[fever]]. Inhibition of [[cyclooxygenase]], specifically the inducible COX-2 isoform, is the hallmark of [[NSAID]]s (non-steroidal anti-inflammatory drugs), such as [[aspirin]]. COX-2 is responsible for pain and inflammation, while COX-1 is responsible for platelet clotting actions. Prostanoids activate the PPAR<sub>γ</sub> members of the steroid/thyroid family of [[Nuclear receptor|nuclear hormone receptors]], directly influencing [[Transcription (genetics)|gene transcription]].<ref name=Bos>{{cite journal |author=Bos C, Richel D, Ritsema T, Peppelenbosch M, Versteeg H |title=Prostanoids and prostanoid receptors in signal transduction |journal=Int J Biochem Cell Biol |volume=36 |issue=7 |pages=1187–205 |year=2004 |pmid=15109566 |doi=10.1016/j.biocel.2003.08.006}}</ref> ===Action of leukotrienes=== {{main|Leukotriene}} Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC<sub>4</sub> in [[luteinizing hormone]] secretion.<ref name=Samuelsson>{{cite journal|journal=Science |year= 1987|month=09-04 |volume= 237|number= 4819|pages=1171–1176| doi= 10.1126/science.2820055|title=Leukotrienes and lipoxins: structures, biosynthesis, and biological effects|author=Samuelsson, SE Dahlen, JA Lindgren, CA Rouzer, and CN Serhan |url=http://www.sciencemag.org/cgi/content/abstract/237/4819/1171|accessdate=2007-01-22|pmid=2820055}}</ref> LTB<sub>4</sub> causes adhesion and [[chemotaxis]] of leukocytes and stimulates aggregation, enzyme release, and generation of [[superoxide]] in [[neutrophil]]s.<ref name=Samuelsson83>{{cite journal|journal=Science |month=May|year= 1983|volume= 220|issue=4597|pages=568–575|doi=10.1126/science.6301011|title=Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation|author=Samuelsson B |url=http://www.sciencemag.org/cgi/content/abstract/sci;220/4597/568|pmid=6301011}}</ref> Blocking leukotriene receptors can play a role in the management of [[inflammatory disease]]s such as [[asthma]] (by the drugs [[montelukast]] and [[zafirlukast]]), [[psoriasis]], and [[rheumatoid arthritis]]. The [[slow reacting substance of anaphylaxis]] comprises the cysteinyl leukotrienes. These have a clear role in [[Pathophysiology|pathophysiological]] conditions such as asthma, [[Hay fever| allergic rhinitis]] and other nasal allergies, and have been implicated in [[atherosclerosis]] and inflammatory [[Digestive disease|gastrointestinal diseases]].<ref name=Capra>{{cite journal |author=Capra V |title=Molecular and functional aspects of human cysteinyl leukotriene receptors |journal=Pharmacol Res |volume=50 |issue=1 |pages=1–11 |year=2004 |pmid=15082024 |doi=10.1016/j.phrs.2003.12.012}}</ref> They are potent bronchoconstrictors, increase vascular permeability in postcapillary [[venule]]s, and stimulate [[mucus]] secretion. They are released from the lung tissue of asthmatic subjects exposed to specific allergens and play a pathophysiological role in [[Allergy|immediate hypersensitivity]] reactions.<ref name=Samuelsson83/> Along with PGD, they function in [[effector cell]] trafficking, antigen presentation, immune cell activation, [[Osteocyte|matrix deposition]], and [[fibrosis]].<ref name=Boyce>{{cite journal |author=Boyce J |title=Eicosanoid mediators of mast cells: receptors, regulation of synthesis, and pathobiologic implications |journal=Chem Immunol Allergy |volume=87 |issue= |pages=59–79 |year=2005 |pmid=16107763 |doi=10.1159/000087571}}</ref> ==History== In [[1930]], gynecologist Raphael Kurzrok and pharmacologist Charles Leib characterized [[prostaglandin]] as a component of semen. Between [[1929]] and [[1932]], Burr and Burr showed that restricting fat from animal's diets led to a deficiency disease, and first described the [[essential fatty acid]]s.<ref name=Burr>{{cite journal | author=Burr, G.O. and Burr, M.M. |year=1930 |url=http://www.jbc.org/cgi/reprint/97/1/1.pdf |accessdate=2007-01-17 | title= On the nature and role of the fatty acids essential in nutrition | journal=J. Biol. Chem.| volume=86 |issue=587|format=PDF}}</ref> In [[1935]], [[Ulf von Euler|von Euler]] identified prostaglandin. In [[1964]], [[Sune Bergström|Bergström]] and [[Bengt I. Samuelsson|Samuelsson]] linked these observations when they showed that the "classical" eicosanoids were derived from arachidonic acid, which had earlier been considered to be one of the essential fatty acids.<ref name=Bergström>{{cite journal | author=Bergström, S., Danielsson, H. and Samuelsson, B. | journal= Biochim. Biophys. Acta |volume=90 |issue=207 |year=1964 | title=The enzymatic formation of prostaglandin E2 from arachidonic acid | pmid=14201168}}</ref> In 1971, [[John Robert Vane|Vane]] showed that aspirin and similar drugs inhibit prostaglandin synthesis.<ref name=Vane>{{cite journal | author=Vane, J. R. | pages=232–5 | pmid=5284360 | year = 1971 | month= June | day= 23 | title= Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs | journal=Nature New Biol. |volume= 231 |issue=25 }}</ref> Von Euler received the [[Nobel Prize]] in medicine in [[1970]], which Samuelsson, Vane, and Bergström also received in [[1982]]. [[Elias James Corey| E. J. Corey]] received it in chemistry in [[1990]] largely for his synthesis of prostaglandins. ==References== <div class="references-small" style="-moz-column-count:2; column-count:2;"> <references/> </div> ==External links== * {{MeshName|Eicosanoids}} {{Lipids}} {{Autacoids}} {{Eicosanoids}} [[Category:Eicosanoids| ]] {{Link FA|es}} [[ca:Icosanoide]] [[de:Eikosanoide]] [[es:Eicosanoide]] [[fr:Eïcosanoïde]] [[it:Eicosanoidi]] [[nl:Eicosanoïde]] [[ja:エイコサノイド]] [[pl:Eikozanoidy]] [[pt:Eicosanóide]] [[ru:Эйкозаноиды]] [[fi:Eikosanoidi]]