Eicosanoid

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Eicosanoids
)
DGLA
.

Eicosanoids are

endocrine
agents to control the function of distant cells.

There are multiple subfamilies of eicosanoids, including most prominently the prostaglandins, thromboxanes, leukotrienes, lipoxins, resolvins, and eoxins. For each subfamily, there is the potential to have at least 4 separate series of metabolites, two series derived from ω-6 PUFAs (arachidonic and dihomo-gamma-linolenic acids), one series derived from the ω-3 PUFA (eicosapentaenoic acid), and one series derived from the ω-9 PUFA (mead acid). This subfamily distinction is important. Mammals, including humans, are unable to convert ω-6 into ω-3 PUFA. In consequence, tissue levels of the ω-6 and ω-3 PUFAs and their corresponding eicosanoid metabolites link directly to the amount of dietary ω-6 versus ω-3 PUFAs consumed.[1] Since certain of the ω-6 and ω-3 PUFA series of metabolites have almost diametrically opposing physiological and pathological activities, it has often been suggested that the deleterious consequences associated with the consumption of ω-6 PUFA-rich diets reflects excessive production and activities of ω-6 PUFA-derived eicosanoids, while the beneficial effects associated with the consumption of ω-3 PUFA-rich diets reflect the excessive production and activities of ω-3 PUFA-derived eicosanoids.[2][3][4][5] In this view, the opposing effects of ω-6 PUFA-derived and ω-3 PUFA-derived eicosanoids on key target cells underlie the detrimental and beneficial effects of ω-6 and ω-3 PUFA-rich diets on inflammation and allergy reactions, atherosclerosis, hypertension, cancer growth, and a host of other processes.

Nomenclature

Fatty acid sources

"Eicosanoid" (from

polyunsaturated fatty acids
) of 20 carbon units in length that have been metabolized or otherwise converted to oxygen-containing products. The PUFA precursors to the eicosanoids include:

  • Arachidonic acid (AA), i.e. 5Z, 8Z,11Z,14Z-eicosatetraenoic acid is an ω-6 fatty acid with four double bonds in the cis configuration (denoted Z in E–Z notation), each located between carbons 5-6, 8-9, 11-12, and 14-15 (see carbon numbering).
  • Adrenic acid
    (AdA), 7,10,13,16-docosatetraenoic acid, is an ω-6 fatty acid with four cis double bounds, each located between carbons 7-8, 10-11, 13-14, and 17-18.
  • Eicosapentaenoic acid (EPA), i.e.i.e. 5Z, 8Z,11Z,14Z,17Z-eicosapentaenoic acid is an ω-3 fatty acid with five cis double bonds, each located between carbons 5-6, 8-9, 11-12, 14-15, and 17-18.
  • Dihomo-gamma-linolenic acid
    (DGLA), 8Z, 11Z,14Z-eicosatrienoic acid is an ω-6 fatty acid with three cis double bonds, each located between carbons 8-9, 11-12, and 14-15.
  • Mead acid, i.e. 5Z,8Z,11Z-eicosatrienoic acid, is an ω-9 fatty acid containing three cis double bonds, each located between carbons 5-6, 8-9, and 11-12.

Abbreviation

A particular eicosanoid is denoted by a four-character abbreviation, composed of:

  • its two-letter abbreviation (LT, EX or PG, as described below),[7]
  • one A-B-C sequence-letter,[8]
  • A subscript or plain script number following the designated eicosanoid's trivial name indicates the number of its double bonds. Examples are:
    • The EPA-derived prostanoids have three double bonds (e.g. PGG3 or PGG3) while leukotrienes derived from EPA have five double bonds (e.g. LTB5 or LTB5).
    • The AA-derived prostanoids have two double bonds (e.g. PGG2 or PGG2) while their AA-derived leukotrienes have four double bonds (e.g. LTB4 or LTB4).
  • Hydroperoxy-, hydroxyl-, and oxo-eicosanoids possess a hydroperoxy (-OOH), hydroxy (-OH), or oxygen atom (=O) substituents link to a PUFA carbon by a single (-) or double (=) bond. Their trivial names indicate the substituent as: Hp or HP for a hydroperoxy residue (e.g. 5-hydroperooxy-eicosatraenoic acid or 5-HpETE or 5-HPETE); H for a hydroxy residue (e.g. 5-hydroxy-eicosatetraenoic acid or 5-HETE); and oxo- for an oxo residue (e.g. 5-oxo-eicosatetraenioic acid or 5-oxo-ETE or 5-oxoETE). The number of their double bounds is indicated by their full and trivial names: AA-derived hydroxy metabolites have four (i.e. 'tetra' or 'T') double bonds (e.g. 5-hydroxy-eicosatetraenoic acid or 5-HETE; EPA-derived hydroxy metabolites have five ('penta' or 'P') double bonds (e.g. 5-hydroxy-eicosapentaenoic acid or 5-HEPE); and DGLA-derived hydroxy metabolites have three ('tri' or 'Tr') double bonds (e.g. 5-hydroxy-eicosatrienoic acid or 5-HETrE).

The stereochemistry of the eicosanoid products formed may differ among the pathways. For prostaglandins, this is often indicated by Greek letters (e.g. PGF versus PGF). For hydroperoxy and hydroxy eicosanoids an S or R designates the chirality of their substituents (e.g. 5S-hydroxy-eicosateteraenoic acid [also termed 5(S)-, 5S-hydroxy-, and 5(S)-hydroxy-eicosatetraenoic acid] is given the trivial names of 5S-HETE, 5(S)-HETE, 5S-HETE, or 5(S)-HETE). Since eicosanoid-forming enzymes commonly make S isomer products either with marked preference or essentially exclusively, the use of S/R designations has often been dropped (e.g. 5S-HETE is 5-HETE). Nonetheless, certain eicosanoid-forming pathways do form R isomers and their S versus R isomeric products can exhibit dramatically different biological activities.[9] Failing to specify S/R isomers can be misleading. Here, all hydroperoxy and hydroxy substituents have the S configuration unless noted otherwise.

Classic eicosanoids

Current usage limits the term eicosanoid to:

Hydroxyeicosatetraenoic acids, leukotrienes, eoxins and prostanoids are sometimes termed "classic eicosanoids"[18][19][20]

Nonclassic eicosanoids

In contrast to the classic eicosanoids, several other classes of PUFA metabolites have been termed 'novel', 'eicosanoid-like' or 'nonclassic eicosanoids'.[21][22][23][24] These included the following classes:

Metabolism of eicosapentaenoic acid to HEPEs, leukotrienes, prostanoids, and epoxyeicosatetraenoic acids as well as the metabolism of dihomo-gamma-linolenic acid to prostanoids and mead acid to 5(S)-hydroxy-6E,8Z,11Z-eicosatrienoic acid (5-HETrE), 5-oxo-6,8,11-eicosatrienoic acid (5-oxo-ETrE), LTA3, and LTC3 involve the same enzymatic pathways that make their arachidonic acid-derived analogs.

Biosynthesis

Eicosanoids typically are not stored within cells but rather synthesized as required. They derive from the fatty acids that make up the cell membrane and nuclear membrane. These fatty acids must be released from their membrane sites and then metabolized initially to products which most often are further metabolized through various pathways to make the large array of products we recognize as bioactive eicosanoids.

Fatty acid mobilization

Eicosanoid biosynthesis begins when a cell is activated by mechanical trauma, ischemia, other physical perturbations, attack by pathogens, or stimuli made by nearby cells, tissues, or pathogens such as chemotactic factors, cytokines, growth factors, and even certain eicosanoids. The activated cells then mobilize enzymes, termed phospholipase A2's (PLA2s), capable of releasing ω-6 and ω-3 fatty acids from membrane storage. These fatty acids are bound in ester linkage to the SN2 position of membrane phospholipids; PLA2s act as esterases to release the fatty acid. There are several classes of PLA2s with type IV cytosolic PLA2s (cPLA2s) appearing to be responsible for releasing the fatty acids under many conditions of cell activation. The cPLA2s act specifically on phospholipids that contain AA, EPA or GPLA at their SN2 position. cPLA2 may also release the lysophospholipid that becomes platelet-activating factor.[28]

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 COX) add molecular oxygen (O2). Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidations proceed with high stereoselectivity (enzymatic oxidations are considered practically stereospecific).

Four families of enzymes initiate or contribute to the initiation of the catalysis of fatty acids to eicosanoids:

Two different enzymes may act in series on a PUFA to form more complex metabolites. For example, ALOX5 acts with ALOX12 or aspirin-treated COX-2 to metabolize arachidonic acid to lipoxins and with cytochrome P450 monooxygenase(s), bacterial cytochrome P450 (in infected tissues), or aspirin-treated COX2 to metabolize eicosapentaenoic acid to the E series resolvins (RvEs) (see Specialized pro-resolving mediators). When this occurs with enzymes located in different cell types and involves the transfer of one enzyme's product to a cell which uses the second enzyme to make the final product it is referred to as transcellular metabolism or transcellular biosynthesis.[31]

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—there are at least eight proteins activated to coordinate generation of leukotrienes. Several of these exist in multiple isoforms.[5]

Oxidation by either COX or lipoxygenase releases reactive oxygen species (ROS) and the initial products in eicosanoid generation are themselves highly reactive peroxides. LTA4 can form adducts with tissue DNA. Other reactions of lipoxygenases generate cellular damage; murine models implicate 15-lipoxygenase in the pathogenesis of atherosclerosis.[32][33] The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage. The enzymes that are biosynthetic for eicosanoids (e.g.,

carrier proteins
) belong to families whose functions are involved largely with cellular detoxification. This suggests that eicosanoid signaling might 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 DNA-transcription there; LTB4 is ligand for PPARα.[3] (See diagram at PPAR).

Structures of selected eicosanoids
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.

Prostanoid pathways

Both COX1 and COX2 (also termed prostaglandin-endoperoxide synthase-1 (

Thromboxane synthase which converts PGH2 to TXA2 (subsequent products in this pathway include TXB2); and e) Prostacyclin synthase which converts PGH2 to PGI2 (subsequent products in this pathway include 6-keto-PGFα.[34][35] These pathways have been shown or in some cases presumed to metabolize eicosapentaenoic acid to eicosanoid analogs of the sited products that have three rather than two double bonds and therefore contain the number 3 in place of 2 attached to their names (e.g. PGE3 instead of PGE2).[36]

The PGE2, PGE1, and PGD2 products formed in the pathways just cited can undergo a spontaneous dehydration reaction to form PGA2, PGA1, and PGJ2, respectively; PGJ2 may then undergo a spontaneous isomerization followed by a dehydration reaction to form in series Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2.[37]

PGH2 has a 5-carbon ring bridged by molecular oxygen. Its derived PGS have lost this oxygen bridge and contain a single, unsaturated 5-carbon ring with the exception of thromboxane A2 which possesses a 6-member ring consisting of one oxygen and 5 carbon atoms. The 5-carbon ring of prostacyclin is conjoined to a second ring consisting of 4 carbon and one oxygen atom. And, the 5 member ring of the cyclopentenone prostaglandins possesses an unsaturated bond in a conjugated system with a carbonyl group that causes these PGs to form bonds with a diverse range of bioactive proteins (for more see the diagrams at Prostanoid).

Hydroxyeicosatetraenoate (HETE) and leukotriene (LT) pathways

The enzyme

LTE4.[39][40] The decision to form LTB4 versus LTC4 depends on the relative content of LTA4 hydrolase versus LTC4 synthase (or glutathione S-transferase in cells; eosinophils, mast cells, and alveolar macrophages possess relatively high levels of LTC4 synthase and accordingly form LTC4 rather than or to a far greater extent than LTB4. 5-LOX may also work in series with cytochrome P450 oxygenases or aspirin-treated COX2 to form Resolvins RvE1, RvE2, and 18S-RvE1 (see Specialized pro-resolving mediators § EPA-derived resolvins
).

The enzyme

12-hydroxyeicosatetraenoic acid (12-HETE) or further metabolized to hepoxilins (Hx) such as HxA3 and HxB.[41][42]

The enzymes

The 15-lipoxygenases (particularly ALOX15) may also act in series with 5-lipoxygenase, 12-lipoxygenase, or aspirin-treated COX2 to form the lipoxins and epi-lipoxins or with P450 oxygenases or aspirin-treated COX2 to form Resolvin E3 (see Specialized pro-resolving mediators § EPA-derived resolvins).

A subset of

20-hydroxyeicosatetraenoic acid (20-HETE) and 19-hydroxyeicosatetraenoic acid by an omega oxidation reaction.[45]

Epoxyeicosanoid pathway

The human cytochrome P450 (CYP) epoxygenases, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, and CYP2S1 metabolize arachidonic acid to the non-classic epoxyeicosatrienoic acids (EETs) by converting one of the fatty acid's double bonds to its epoxide to form one or more of the following EETs, 14,15-ETE, 11,12-EET, 8,9-ETE, and 4,5-ETE.[46][47] 14,15-EET and 11,12-EET are the major EETs produced by mammalian, including human, tissues.[47][48][49][50][51] The same CYPs but also CYP4A1, CYP4F8, and CYP4F12 metabolize eicosapentaenoic acid to five epoxide epoxyeicosatetraenoic acids (EEQs) viz., 17,18-EEQ, 14,15-EEQ, 11,12-EEQ. 8,9-EEQ, and 5,6-EEQ.[52]

Function, pharmacology, and clinical significance

The following table lists a sampling of the major eicosanoids that possess clinically relevant biological activity, the cellular receptors (see Cell surface receptor) that they stimulate or, where noted, antagonize to attain this activity, some of the major functions which they regulate (either promote or inhibit) in humans and mouse models, and some of their relevancies to human diseases.

Eicosanoid Targeted receptors Functions regulated Clinical relevancy
PGE2
PTGER4
inflammation; fever; pain perception;
parturition
NSAIDs inhibit its production to reduce inflammation, fever, and pain; used to promote labor in childbirth; an abortifacient[35][53][54]
PGD2 Prostaglandin DP1 receptor 1, Prostaglandin DP2 receptor allergy reactions; allodynia; hair growth NSAIDs may target it to inhibit allodynia and
male-pattern hair loss[35][55][56][57][58]
TXA2 Thromboxane receptor α and β blood platelet aggregation; blood clotting; allergic reactions NSAIDs inhibit its production to reduce incidence of
heart attacks[35][59]
PGI2 Prostacyclin receptor platelet aggregation, vascular smooth muscle contraction PGI2 analogs used to treat vascular disorders like
Buerger's disease[60][61][62]
15-d-Δ12,14-PGJ2 inhibits inflammation and cell growth inhibits diverse inflammatory responses in animal models; structural model for developing anti-inflammatory agents[10][57][58]
20-HETE ? vasoconstriction, inhibits platelets inactivating mutations in the 20-HETE-forming enzyme, CYP2U1, associated with hereditary spastic paraplegia[63]
5-Oxo-ETE
OXER1
chemotactic factor for and activator of eosinophils studies needed to determine if inhibiting its production or action inhibits allergic reactons[30]
LTB4
LTB4R2
chemotactic factor for and activator of leukocytes; inflammation studies to date shown no clear benefits of LTB4 receptor antagonists for human inflammatory diseases[64][65][66]
LTC4
CYSLTR2, GPR17
vascular permeability; vascular smooth muscle contraction; allergy antagonists of CYSLTR1 used in asthma as well as other allergic and allergic-like reactions[67][68]
LTD4
CYSLTR2, GPR17
vascular permeability; vascular smooth muscle contraction; allergy antagonists of CYSLTR1 used in asthma as well as other allergic and allergic-like reactions[64]
LTE4
GPR99
increases vascular permeability and airway mucin secretion thought to contribute to asthma as well as other allergic and allergic-like reactions[69]
LxA4
FPR2
inhibits functions of pro-inflammatory cells Specialized pro-resolving mediators class of inflammatory reaction suppressors[70][71]
LxB4
AHR
inhibits functions of pro-inflammatory cells Specialized pro-resolving mediators class of inflammatory reaction suppressors[70][71]
RvE1
TNFR
inhibits functions of pro-inflammatory cells Specialized pro-resolving mediators class of inflammatory reaction suppressors; also suppresses pain perception[72][73][74]
RvE2 CMKLR1, receptor antagonist of BLT inhibits functions of pro-inflammatory cells Specialized pro-resolving mediators class of inflammatory reaction suppressors[70][71][74][75]
14,15-EET ? vasodilation, inhibits platelets and pro-inflammatory cells role(s) in human disease not yet proven[76][77]

Prostanoids

Many of the prostanoids are known to mediate local symptoms of

NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin. Prostanoids also activate the PPARγ members of the steroid/thyroid family of nuclear hormone receptors, and directly influence gene transcription.[78]
Prostanoids have numerous other relevancies to clinical medicine as evidence by their use, the use of their more stable pharmacological analogs, of the use of their receptor antagonists as indicated in the following chart.

Medicine Type Medical condition or use Medicine Type Medical condition or use
Alprostadil
PGE1
Erectile dysfunction, maintaining a patent ductus arteriosus in the fetus Beraprost PGI1 analog Pulmonary hypertension, avoiding reperfusion injury
Bimatoprost PGF2α analog Glaucoma, ocular hypertension Carboprost PGF2α analog Labor induction, abortifacient in early pregnancy
Dinoprostone
PGE2 Labor induction Iloprost PGI2 analog
Pulmonary artery hypertension
Latanoprost PGF2α analog Glaucoma, ocular hypertension Misoprostol PGE1 analog
Travoprost PGF2α analog Glaucoma, ocular hypertension U46619 Longer lived TX analog Longer lived TX analog Research only

Cyclopentenone prostaglandins

PGA1, PGA2, PGJ2, Δ12-PGJ2, and 15-deox-Δ12,14-PGJ2 exhibit a wide range of anti-inflammatory and inflammation-resolving actions in diverse animal models.[37] They therefore appear to function in a manner similar to specialized pro-resolving mediators although one of their mechanisms of action, forming covalent bonds with key signaling proteins, differs from those of the specialized pro-resolving mediators.

HETEs and oxo-ETEs

As indicated in their individual Wikipedia pages,

20-hydroxyeicosatetraenoic acid
show numerous activities in animal and human cells as well as in animal models that are related to, for example, inflammation, allergic reactions, cancer cell growth, blood flow to tissues, and/or blood pressure. However, their function and relevancy to human physiology and pathology have not as yet been shown.

Leukotrienes

The three cysteinyl leukotrienes, LTC4, LTD4, and LTE4, are potent bronchoconstrictors, increasers of vascular permeability in postcapillary

urticarial diseases such as hives.[84]

Lipoxins and epi-lipoxins

LxA4, LxB4, 15-epi-LxA4, and 15-epi-LXB4, like other members of the

eczema in a study of 60 infants[85] and, in another study, inhaled LXA4 decreased LTC4-initiated bronchoprovocation in patients with asthma.[86]

Eoxins

The eoxins (EXC4, EXD4, EXE5) are newly described. They stimulate vascular permeability in an ex vivo human vascular endothelial model system,

Hodgkins disease.[89]
However, the clinical significance of eoxins has not yet been demonstrated.

Resolvin metabolites of eicosapentaenoic acid

RvE1, 18S-RvE1, RvE2, and RvE3, like other members of the specialized pro-resolving mediators) class of eicosanoids, possess anti-inflammatory and inflammation resolving activity. A synthetic analog of RvE1 is in clinical phase III testing (see Phases of clinical research) for the treatment of the inflammation-based dry eye syndrome; along with this study, other clinical trials (NCT01639846, NCT01675570, NCT00799552 and NCT02329743) using an RvE1 analogue to treat various ocular conditions are underway.[86] RvE1 is also in clinical development studies for the treatment of neurodegenerative diseases and hearing loss.[90]

Other metabolites of eicosapentaenoic acid

The metabolites of eicosapentaenoic acid that are analogs of their arachidonic acid-derived prostanoid, HETE, and LT counterparts include: the 3-series prostanoids (e.g. PGE3, PGD3, PGF3α, PGI3, and TXA3), the hydroxyeicosapentaenoic acids (e.g. 5-HEPE, 12-HEPE, 15-HEPE, and 20-HEPE), and the 5-series LTs (e.g. LTB5, LTC5, LTD5, and LTE5). Many of the 3-series prostanoids, the hydroxyeicosapentaenoic acids, and the 5-series LT have been shown or thought to be weaker stimulators of their target cells and tissues than their arachidonic acid-derived analogs. They are proposed to reduce the actions of their aracidonate-derived analogs by replacing their production with weaker analogs.[91][92] Eicosapentaenoic acid-derived counterparts of the Eoxins have not been described.

Epoxyeicosanoids

The epoxy eicosatrienoic acids (or EETs)—and, presumably, the epoxy eicosatetraenoic acids—have

tumors, promote the growth of new blood vessels, in the central nervous system, regulate the release of neuropeptide hormones, and in the peripheral nervous system inhibit or reduce pain perception.[46][47][49]

The ω-3 and ω-6 series

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.

— Kevin Fritsche, Fatty Acids as Modulators of the Immune Response[93]

Arachidonic acid (AA; 20:4 ω-6) sits at the head of the "arachidonic acid cascade" – more than twenty eicosanoid-mediated signaling paths controlling a wide array of cellular functions, especially those regulating inflammation, immunity, and the central nervous system.[4]

In the inflammatory response, two other groups of dietary fatty acids form cascades that parallel and compete with the arachidonic acid cascade.

mental illnesses
.

The U.S.

National Library of Medicine state that there is 'A' level 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.[94]

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.[93] Of these, the action on eicosanoids is the best explored.

Mechanisms of ω-3 action

EFA sources: Essential fatty acid production and metabolism to form eicosanoids. At each step, the ω-3 and ω-6 cascades compete for the enzymes.

In general, the eicosanoids derived from AA promote inflammation, and those from EPA and from

GLA (via DGLA) are less inflammatory, or inactive, or even anti-inflammatory and pro-resolving
.

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—Dietary ω-3 decreases tissue concentrations of AA, so there is less to form ω-6 eicosanoids.
  • Competitive inhibition—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—Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts.

Role in inflammation

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.

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 loses 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.

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 acids.[95] In 1935, von Euler identified prostaglandin. In 1964, Bergström and 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.[96] In 1971,

Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis.[97] 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.

See also

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External links