In biochemistry, eicosanoids are signaling molecules made by oxygenation of twenty-carbon essential fatty acids, (EFAs). They exert complex control over many bodily systems, mainly in inflammation or 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 (ω-3) or 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 NSAIDs act by downregulating eicosanoid synthesis.
There are four families of eicosanoids—the prostaglandins, prostacyclins, the thromboxanes and the leukotrienes. 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.
Current usage limits the term to the leukotrienes (LT) and three types of prostanoids—prostaglandins (PG) prostacyclins (PGI), and thromboxanes (TX). This is the definition used in this article. However, several other classes can technically be termed eicosanoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epi-lipoxins, epoxyeicosatrienoic acids (EETs) and endocannabinoids. LTs and prostanoids are sometimes termed 'classic eicosanoids' in contrast to the 'novel', 'eicosanoid-like' or 'nonclassic eicosanoids'. A particular eicosanoid is denoted by a four-character abbreviation, composed of:
Furthermore, stereochemistry may differ among the pathways, indicated by Greek letters, e.g. for (PGF2α).
Eicosanoid biosynthesis begins 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.) Phospholipase is released at the cell membrane and travels to the nuclear membrane. There, it frees 20-carbon essential fatty acids. 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 Pathways table. The classical pathways add molecular oxygen (O2) via Lipoxygenase or Cyclooxygenase. Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidation proceeds with high stereospecificity.
Nevertheless, there is an advantage in the proximity to the nucleus, since, PGs and LTs may signal or regulate DNA-transcription there; For instance, LTB4 is a ligand for PPARα, (see diagram at PPAR).
There are elaborate mechanisms to prevent unwanted oxidation. COX, the lipoxygenases and the phospholipases are tightly controlled—there are at least eight proteins activated to coordinate generation of leukotrienes. Several of these exist in multiple isoforms. 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.
|Prostaglandin E1. The 5-member ring is characteristic of the class.|| Thromboxane A2. Oxygens|
have moved into the ring.
|Leukotriene B4. Note the 3 conjugated double bonds.|
|Prostacyclin I2. The second ring distinguishes it from the prostaglandins.||Leukotriene E4, an example of a cysteinyl leukotriene.|
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.
|PGD2||Promotion of sleep||TXA2|| Stimulation of platelet|
|PGE2|| Smooth muscle contraction; |
inducing pain, heat, fever;
|PGF2α||Uterine contraction||LTB4||Leukocyte chemotaxis|
|PGI2||Inhibition of platelet aggregation; |
vasodilation; embryo implantation
|Cysteinyl-LTs|| Anaphylaxis; bronchial smooth|
|†Shown eicosanoids are AA-derived; EPA-derived generally have weaker activity|
Eicosanoids have a short half-life, ranging from seconds to minutes. Dietary antioxidants inhibit the generation of some inflammatory eicosanoids, e.g. trans-resveratrol against thromboxane and some leukotrienes. Most eicosanoid receptors are members of the G protein-coupled receptor superfamily; see the Receptors table or the article eicosanoid receptors.
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 ResponseArachidonic acid (AA; 20:4 ω-6) sits at the head of the 'arachidonic acid cascade'—more than twenty different eicosanoid-mediated signaling paths controlling a wide array of cellular functions, especially those regulating inflammation, immunity and the central nervous system.
In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. EPA (20:5 ω-3) provides the most important competing cascade. DGLA (20:3 ω-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 illnesses.
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 primary prevention of cardiovascular disease, rheumatoid arthritis and protection from ciclosporin toxicity in organ transplant patients. They also note more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders.
Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They
(a) alter membrane composition and function, including the composition of lipid rafts;
(b) change cytokine biosynthesis and (c) directly activate gene transcription. Of these, the action on eicosanoids is the best explored.
The eicosanoids from AA generally promote inflammation. Those from EPA and from 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:
Redness—An insect's sting will trigger the classic inflammatory response. Short acting vasoconstrictors — TXA2—are released quickly after the injury. The site may momentarily turn pale. Then TXA2 mediates the release of the vasodilators PGE2 and LTB4. The blood vessels engorge and the injury reddens.
Swelling—LTB4 makes the blood vessels more permeable. Plasma leaks out into the connective tissues, and they swell. The process also looses pro-inflammatory cytokines.
Pain—The cytokines increase COX-2 activity. This elevates levels of PGE2, sensitizing pain neurons.
Heat—PGE2 is also a potent pyretic agent. Aspirin and NSAIDS—drugs that block the COX pathways and stop prostanoid synthesis—limit fever or the heat of localized inflammation.
|Medicine||Type||Medical condition or use|
|Alprostadil||PGI1|| Erectile dysfunction, maintaining a |
patent ductus arteriosus in the fetus
|Beraprost||PGI1 analog|| Pulmonary hypertension, avoiding|
|Bimatoprost||PG analog||Glaucoma, ocular hypertension|
|Carboprost||PG analog|| Labor induction, abortifacient|
in early pregnancy
|Iloprost||PGI2 analog||Pulmonary arterial hypertension|
|Latanoprost||PG analog||Glaucoma, ocular hypertension|
|Misoprostol||PGE1 analog|| Stomach ulcers, labor induction, |
|Montelukast|| LT receptor |
|Asthma, seasonal allergies|
|Travoprost||PG analog||Glaucoma, ocular hypertension|
|Treprostinil||PGI analog||Pulmonary hypertension|
|U46619|| Longer lived |
|Zafirlukast|| LT receptor |
Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC4 in luteinizing hormone secretion. LTB4 causes adhesion and chemotaxis of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils. Blocking leukotriene receptors can play a role in the management of inflammatory diseases 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 pathophysiological conditions such as asthma, allergic rhinitis and other nasal allergies, and have been implicated in atherosclerosis and inflammatory gastrointestinal diseases. They are potent bronchoconstrictors, increase vascular permeability in postcapillary venules, and stimulate mucus secretion. They are released from the lung tissue of asthmatic subjects exposed to specific allergens and play a pathophysiological role in immediate hypersensitivity reactions. Along with PGD, they function in effector cell trafficking, antigen presentation, immune cell activation, matrix deposition, and fibrosis.