View source for Eicosanoid

{{SI}}


==Overview==
In biochemistry, '''eicosanoids''' are [[lipid signaling|signaling molecules]] derived from [[omega-3 fatty acid|omega-3]] (&omega;-3) or [[omega-6 fatty acid|omega-6]] (&omega;-6) fats.
They exert complex control over many bodily systems, especially in [[inflammation]], [[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.

The &omega;-6 eicosanoids are generally pro-inflammatory; &omega;-3's are much less so.  
The amounts 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 [[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 &omega;-3 or &omega;-6 [[essential fatty acid]].  These series' different activities largely explain the health effects of &omega;-3 and &omega;-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}}</ref><ref name=Funk>{{cite journal
  | author=Funk, Colin D. | journal=Science |year=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}}</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 = 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 
  |accessdate=June 1|accessyear=2006}}</ref> for oxygenated derivatives of three different 20-carbon [[essential fatty acids]]:
*[[Eicosapentaenoic acid]] ('''EPA'''), an &omega;-3 fatty acid with 5 [[double bond]]s;
*[[Arachidonic acid]] ('''AA'''), an &omega;-6 fatty acid, with 4 double bonds;
*[[Dihomo-gamma-linolenic acid]] ('''DGLA'''), an &omega;-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, [[epoxyeicosatrienoic acid]]s (EETs) and some [[Cannabinoid#Endogenous Cannabinoids|endocannabinoids]].
 
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 DGLA-derived prostanoids have one double bond, (e.g. PGE<sub>1</sub>, TXA<sub>1</sub>).  
Commenting this out because the section's already too cluttered and it only needs to introduce the terminology system, not exhaustively list it.
  -->
* 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>).
Two families of [[enzymes]] catalyze fatty acid oxygenation to produce the eicosanoids:
* [[Cyclooxygenase]], or <i><b>COX</b></i>, which comes in at least three [[isoform]]s, ''COX-1, -2, -3''  &ndash; leading to the prostanoids.<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}}</ref>
* [[Lipoxygenase]], in several forms.  5-lipoxygenase ('''5-LO''') generates the leukotrienes. 
<!-- 
**Use this in the biosynthesis sub-article**
The [[International Union of Pure and Applied Chemistry|IUPAC]] and the [[International Union of Biochemistry and Molecular Biology|IUBMB]] use the equivalent term '''Icosanoid'''.<ref name=CyberlipidP>{{cite web
  | author=Cyberlipid Center| title=Prostanoids
  | url= http://www.cyberlipid.org/prost1/pros0001.htm#9 | accessdate=June 1| accessyear=2006}}</ref>
There are exceptions to this pattern, some of which indicate [[stereochemistry]] (PGF<sub>2&alpha;</sub>).
5-LO acts at the fifth carbon from the [[Carboxylic acid|carboxyl group]].  
Other lipoxygenases&mdash;8-LO, 12-LO and 15-LO&mdash;make other eicosanoid-like products.  
To act, 5-LO uses the nuclear-membrane [[enzyme]] [[5-Lipoxygenase activating protein|5-lipoxygenase-activating protein]] ('''FLAP'''), first to a hydroperoxyeicosatetraenoic acid ('''HPETE'''), then to the first leuokotriene, LTA.
Production of PGE<sub>2</sub> in bacterial and viral infections appears to be stimulated by certain cytokines, e.g., [[interleukin-1]].<ref name=University/>
-->

==Biosynthesis==
{| class="wikitable" style="float:center"
|+Eicosanoid pathways 
!'Classical' eicosanoids
! colspan=2|Other signaling molecules derived from 20-carbon essential fatty acids
|-
|valign=top|The free fatty acid has two <br>possible ''eicosanoid'' fates:
*[[Lipoxygenases|5-lipoxygenase]] pathway:
**[[Leukotriene]]s
*[[Cyclooxygenase]] pathway <br>("prostanoids"):
**[[Prostaglandin]]s
**[[Prostacyclin]]
**[[Thromboxane]]s 
|valign=top| Other oxygenation pathways make<br> related products:
*[[Lipoxygenases|12-lipoxygenase]] pathway:
**[[Hepoxilin]]s
**[[Lipoxin]]s
*[[Cytochrome P450]] pathways:
**[[Epoxyeicosatrienoic acid|EETs]]
*[[Radical (chemistry)|Free radical]] [[Peroxide|peroxidation]]:
**[[Isoprostane]]s
**[[Isofuran]]s
|valign=top|There is also ethanolamide or [[glycerol]]<br>addition:
*[[Anandamide]] and other <br>[[Cannabinoids|endocannabinoids]]
|}
Eicosanoids are a class of oxygenated fatty acids, found widely in a variety of microorganisms, plants and animals.  In humans, eicosanoids are local hormones  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.  They are potent in the [[Concentration#Molarity|nanomolar]] range.  Eicosanoids are not stored within cells, but are [[Biosynthesis|synthesized]] as required.  
They derive from fatty acids which are incorporated as [[ester]]s into larger molecules&mdash;the [[phospholipid]]s and  [[diglyceride|diacylglycerol]]s&mdash;found in the [[cell membrane]] and [[Nuclear envelope|nuclear membrane]].

The first step of eicosanoid biosynthesis occurs when cell is activated by mechanical trauma, cytokines, growth factors or other stimuli.  
(The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.)  This triggers the release of a [[phospholipase]] at the [[cell wall]].  
The phospholipase travels to the [[nuclear membrane]].
There, the phospholipase catalyzes ester [[hydrolysis]] of phospholipid (by [[Phospholipase A|A<sub>2</sub>]]) or diacylglycerol (by [[phospholipase C]]).
This frees a 20-carbon [[essential fatty acid]].  This hydrolysis appears to be the [[rate-determining step]] for eicosanoid formation.  

The fatty acids may be released by any of several phospholipases. 
Of these, type IV cytosolic phospholipase A<sub>2</sub> (cPLA<sub>2</sub>) is the key actor, as cells lacking cPLA<sub>2</sub> are generally devoid of eicosanoid synthesis.  The phospholipase
cPLA<sub>2</sub> is specific for phospholipids that contain AA, EPA or GPLA at the [[Phospholipase A|SN2]] position.
Interestingly, cPLA<sub>2</sub> may also release the lysophospholipid that becomes [[platelet-activating factor]].<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}}</ref>

===Peroxidation and reactive oxygen species===
Next, the free fatty acid is oxygenated along any of several pathways; see the ''Pathways'' table.  The eicosanoid pathways (''via'' [[lipoxygenase]] or [[Cyclooxygenase|COX]]) add [[Oxygen|molecular oxygen]] (O<sub>2</sub>).  Although the fatty acid is [[Symmetry|symmetric]], the resulting eicosanoids are [[Chirality (chemistry)|chiral]]; the oxidation proceeds with high [[stereospecificity]].

The oxidation of lipids is hazardous to cells, particularly when close to the nucleus.
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/>
 
Oxidation by either COX or lipoxygenase releases [[reactive oxygen species]] (ROS) and the initial products in eicosanoid generation are themselves highly reactive [[peroxide]]s.  
LTA<sub>4</sub> can form [[adduct]]s with tissue [[DNA]].  
Other reactions of lipoxygenases 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}}</ref><ref name=Schewe>{{cite journal
  | author=Schewe T.  |journal= Biol Chem. |year= 2002 Mar-Apr| volume= 383|issue= 3-4 |pages: 365-74
  | 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}}</ref>
The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage.
The enzymes which are biosynthetic for eicosanoids (e.g. [[transferase|glutathione-S-transferases]], epoxide [[hydrolase]]s and [[carrier protein]]s) belong to families whose functions are largely involved with cellular detoxification.  
This suggests that eicosanoid signaling may have evolved from the detoxification of ROS.

The cell must realize some benefit from generating lipid hydroperoxides close-by its nucleus.
PGs and LTs  may  signal or regulate [[Transcription (genetics)|DNA-transcription]] there; 
LTB<sub>4</sub> is ligand for [[Peroxisome proliferator-activated receptor|PPAR&alpha;]].<ref name=Funk />
<i>(See diagram at [[Peroxisome_proliferator-activated_receptor | PPAR]]).</i>
{| border=0 width=620 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.png|200px]]
| align="center"| [[Image:Leukotriene B4.svg|200px|]]
|- 
| 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 have moved into the ring. 
| align="center"| Leukotriene B<sub>4</sub>.  Note the three 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.
|}

===Biosynthesis of prostanoids===
:''Several drugs lower inflammation by blocking prostanoid synthesis; see detail at [[Cyclooxygenase]], [[Aspirin]] and [[Non-steroidal anti-inflammatory drug|NSAID]].''
<!--As AA is the most abundant source of ecosanoids, we will discuss reaction pathways in terms of AA and its metabolites.  Unless otherwise noted, EPA, DGLA and their metabolites follow parallel pathways.-->
[[Cyclooxygenase]] (''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.
''(See more detail, including the enzymes involved, in diagrams at [[Prostanoid]].)''

=== Biosynthesis of leukotrienes ===

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>&dagger;</sup><ref name=University />
|-
| 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>2&alpha;</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>&dagger;</sup>Shown eicosanoids are AA-derived; EPA-derived generally have weaker activity</small>
|-
|} </center>
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 Mar 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
   | id=PMID 7554275}}</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>2&alpha;</sub>: FP-(PGF<sub>2&alpha;</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 ===
{{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= 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 &omega;-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 &omega;-3 improves outcomes in [[hypertriglyceridemia]], secondary [[cardiovascular disease]] prevention and [[hypertension]].
There is 'B' level evidence ('good scientific evidence') for increased dietary &omega;-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 &omega;-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 
   | accessyear=2006|accessdate=March 26| date= August 1, 2005}}</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===
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 &omega;-3 and -6 synthesis chains, along with the major eicosanoids from AA, EPA and DGLA. 
[[Image:EFA to Eicosanoids.svg|400px|thumb|right|EFA Souces: Essential fatty acid production and metabolism to form Eicosanoids.  At each step, the &omega;-3 and &omega;-6 cascades compete for the enzymes. ]]

Dietary  &omega;-3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways along the eicosanoid pathways. 
*''Displacement''&mdash;Dietary &omega;-3 decreases tissue concentrations of AA.  Animal studies show that increased  dietary &omega;-3  results in decreased AA in brain  and other tissue.<ref name=Medical>{{cite web 
  |author=Medical Study News| title=Brain fatty acid levels linked to depression 
  |year= 25-May-2005 |accessdate= February 10|accessyear=2006
  |url= http://www.news-medical.net/?id=10398}}
* Who were in turn citing {{cite journal
    |title=Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression 
    |author=Pnina Green, Iris Gispan-Herman and Gal Yadid| accessdate= 2006-02-10 
    |url= http://www.jlr.org/cgi/content/abstract/46/6/1093|year=June 2005}}</ref> [[Linolenic acid]] (18:3 &omega;-3) contributes to this by displacing [[linoleic acid]] (18:2 &omega;-6) from the elongase and [[desaturase]] enzymes that produce AA.  EPA inhibits [[phospholipase]] A2's release of AA from cell membrane.<ref name=Su>{{cite journal
  | author=KP Su, SY Huang, CC Chiu, WW Shen | url=http://nutri.tmu.edu.tw/slide/b2.pdf 
  |title=Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled ...
  |year=2003 |accessdate= 2006-02-22}}</ref>  Other mechanisms involving the transport of EFAs may also play a role.  The reverse is also true &ndash; high dietary linoleic acid decreases the body's conversion of &alpha;-linolenic acid to EPA.  However, the effect is not as strong; the desaturase has a higher affinity for &alpha;-linolenic acid than it has for linoleic acid.<ref name=Phinney>{{cite journal
  | author=Phinney, SD , RS Odin, SB Johnson and RT Holman
  | journal = American Journal of Clinical Nutrition 
  | volume = 51 | pages = 385-392
  |title=Reduced arachidonate in serum phospholipids and cholesteryl esters associated with vegetarian diets in humans
  |url=http://intl.ajcn.org/cgi/content/abstract/51/3/385
  |accessdate=2006-02-11|year=1990}}
* "[D]ietary arachidonic acid enriches its circulating pool in humans; however, 20:5n-3 is not similarly responsive to dietary restriction."</ref> 

*''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.  For example, dietary GLA increases tissue DGLA and lowers TXB<sub>2</sub>.<ref name=Guivernau>{{cite journal
  | author= Guivernau M, Meza N, Barja P, Roman O. |id=PMID 7846101|year=Nov 1994  
  | title= ''Clinical and experimental study on the long-term effect of dietary gamma-linolenic acid on plasma lipids, platelet aggregation, thromboxane formation, and prostacyclin production.'' 
  |accessdate= 2006-02-04}}
* GLA decreases triglycerides, LDL, increases HDL, decreases TXB<sub>2</sub> and other inflammatory markers.  Review article; human and rat studies.</ref><ref name=Karlstaad>{{cite journal
    | title=Effect of intravenous lipid emulsions enriched with gamma-linolenic acid on plasma n-6 fatty acids and prostaglandin biosynthesis after burn and endotoxin injury in rats
    | year= Nov 1993 | id=PMID 8222692 
    | author= Karlstad MD, DeMichele SJ, Leathem WD, Peterson MB.
    | accessdate= February 6 |accessyear=2006}}
* IV Supplementation with gamma-linolenic acid increased serum GLA but did not increase the plasma percentage of arachidonic acid (rat study), decreased TXB<sub>2</sub>.</ref>  Likewise, EPA inhibits the production of series-2 PG and TX.<ref name=Calder>{{cite web
  |author= Calder, Philip C. |year= September 2004 
  |title=n-3 Fatty Acids and Inflammation &ndash; New Twists in an Old Tale|accessdate=February 8|accessyear=2006
  | url=http://fatsoflife.com/articlePrint.asp?id=197}}
* Invited review article, PUFA Newsletter.</ref>  Although DGLA forms no LTs, a DGLA derivative blocks  the transformation of AA to LTs.<ref name=Belch>{{cite journal
  | author= Belch, Jill JF and Alexander Hill| title=Evening primrose oil and borage oil in rheumatologic conditions
  |year=January 2000
  | url= http://www.ajcn.org/cgi/content/full/71/1/352S|accessdate=2006-02-12}}
* "DGLA itself cannot be converted to LTs but can form a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to LTs. Increasing DGLA intake may allow DGLA to act as a competitive inhibitor of 2-series PGs and 4-series LTs and thus suppress inflammation."</ref>  EPA lowers the formation of the AA-derived cysteinyl leukotrienes (series-4 LTC, LTD, LTE) forming the much less active series-5 instead.<ref name=Lee84>{{cite journal
  |journal=: J Clin Invest|year= 1984 |month=Dec|volume=74|issue=6|pages=1922-33.
  |title=Effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils.
  |url= http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=425378&blobtype=pdf
  |author=Lee TH, Mencia-Huerta JM, Shih C, Corey EJ, Lewis RA, Austen KF|id=PMID 6096400|accessdate=2007-01-31}}</ref>  Another &omega;-3 fat, [[Docosahexaenoic acid|DHA]] (22:5 &omega;-3), does not form eicosanoids but inhibits the formation of AA-derived prostanoids.<ref name=Corey2>{{cite journal 
 |author=Corey E, Shih C, Cashman J |url=http://www.pnas.org/cgi/reprint/80/12/3581.pdf
 |title=Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis 
 |journal=Proc Natl Acad Sci U S A |volume=80 |issue=12 |pages=3581-4 |year=1983 |id=PMID 6304720}}</ref>

*''Counteraction''&mdash;Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts.  For example, DGLA yields PGE<sub>1</sub>, which powerfully counteracts PGE<sub>2</sub>.<ref name=Fan>{{cite journal | author=Fan, Yang-Yi and Robert S. Chapkin
  | title=''Importance of Dietary gamma -Linolenic Acid in Human Health and Nutrition''
  | url=http://jn.nutrition.org/cgi/content/full/128/9/1411
  | year= 9 September 1998 | accessdate= 2007-01-05
  | journal =Journal of Nutrition 
  | volume = 128 |issue = 9 |pages = 1411-1414}}
* "[D]ietary GLA increases the content of its elongase product, dihomo-gamma linolenic acid (DGLA), within cell membranes without concomitant changes in arachidonic acid (AA). Subsequently, upon stimulation, DGLA can be converted by inflammatory cells to  15-(S)-hydroxy-8,11,13-eicosatrienoic acid and prostaglandin E1. This is noteworthy because these compounds possess both anti-inflammatory and antiproliferative properties."</ref>  It also yields the leukotriene LTB<sub>5</sub> which impedes the action of the AA-derived LTB<sub>4</sub>.<ref name=Prescott>{{cite journal 
  |author=Prescott S |title=The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils 
  |url= http://www.jbc.org/cgi/reprint/259/12/7615.pdf |journal=J Biol Chem |volume=259 |issue=12 |pages=7615-21 
  |year=1984 |id=PMID 6330066|accessdate=2006-02-12}}</ref>

===Complexity of pathways===
{{Cquote
  |The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with.|40px|40px|Daniele Piomelli|Arachidonic Acid<ref name=Piomelli />}}
Eicosanoid signaling paths are complex. 
It is therefore difficult to characterize the action of any particular eicosanoid.
For example, PGE<sub>2</sub> binds four receptors, dubbed EP<sub>1&ndash;4</sub>.  
Each is coded by a separate gene, and some exist in multiple [[isoform]]s.  
Each EP receptor in turn couples to a [[G protein]].
The EP<sub>2</sub>, EP<sub>4</sub> and one isoform of the EP<sub>3</sub> receptors couple to G<sub>s</sub>. 
This increases intracellular [[Cyclic adenosine monophosphate|cAMP]] and is anti-inflammatory.  
EP<sub>1</sub> and other EP<sub>3</sub> isoforms couple to G<sub>q</sub>.  
This leads to increased intracellular calcium and is pro-inflammatory.  
Finally, yet another EP<sub>3</sub> isoform couples to G<sub>i</sub>, which both decreases cAMP and increases calcium. Many immune-system cells express multiple receptors that couple these apparently opposing pathways.<ref name=Tilley>{{cite journal |author=Tilley S, Coffman T, Koller B |title=Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes |journal=J Clin Invest |volume=108 |issue=1 |pages=15-23 |year=2001 |id=PMID 11435451|url=http://www.jci.org/cgi/reprint/108/1/15 |accessdate=2007-01-30}}</ref>   
Presumably, EPA-derived PGE<sub>3</sub> has a somewhat different effect of on this system, but it is not well-characterized.

===Role in inflammation ===
{| class="wikitable" style="margin: 1em 0 1em 1em; float: right;"
|+Pharmacy: Eicosanoid, eicosanoid analogs and receptor agonists 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]]
|-
|}
[[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.

''[[Erythema|Redness]]''&mdash;An insect's sting will trigger the classic inflammatory response.  Short acting [[vasoconstrictor]]s&mdash;PGI<sub>2</sub> and 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 a also 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 nociception|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  play pivotal functions  inflammation, platelet aggregation, and vasoconstriction/relaxation. Prostanoids activate the PPAR<sub>&gamma;</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 |id=PMID 15109566}}</ref>

===Action of leukotrienes===
:''Main article: [[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}}</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}}</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 |id=PMID 15082024}}</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 |id=PMID 16107763}}</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}}</ref>  
In 1935, von Euler identified prostaglandin.
In 1964, Bergström and Samuelsson linked these observations when they showed that the &quot;classical&quot; 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 
  | id=PMID 14201168}}</ref>
In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis.<ref name=Vane>{{cite journal
  | author=Vane, J. R. | pages=232-5 | id=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.
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| ]]



[[es:Eicosanoide]]
[[fr:Eïcosanoïde]]
[[ja:エイコサノイド]]
[[pl:Eikozanoidy]]
[[pt:Eicosanóide]]

{{WikiDoc Help Menu}}
{{WikiDoc Sources}}