Leukotriene

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LTA4 Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4. Leukotriene A4.svg
LTA4 Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4.
LTB4 Leukotriene B4.svg
LTB4
LTC4 is a cysteinyl leukotriene, as are D4 and E4. Leukotriene C4.svg
LTC4 is a cysteinyl leukotriene, as are D4 and E4.
LTD4 Leukotriene D4.svg
LTD4
LTE4 Leukotriene E4.svg
LTE4

Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase. [1] [2] [3]

Contents

Leukotrienes use lipid signaling to convey information to either the cell producing them (autocrine signaling) or neighboring cells (paracrine signaling) in order to regulate immune responses. The production of leukotrienes is usually accompanied by the production of histamine and prostaglandins, which also act as inflammatory mediators. [4]

One of their roles (specifically, leukotriene D4) is to trigger contractions in the smooth muscles lining the bronchioles; their overproduction is a major cause of inflammation in asthma and allergic rhinitis. [5] Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes. [6]

History and name

The name leukotriene, introduced by Swedish biochemist Bengt Samuelsson in 1979, comes from the words leukocyte and triene (indicating the compound's three conjugated double bonds). What would be later named leukotriene C, "slow reaction smooth muscle-stimulating substance" (SRS) was originally described between 1938 and 1940 by Feldberg and Kellaway. [7] [8] [9] The researchers isolated SRS from lung tissue after a prolonged period following exposure to snake venom and histamine. [9]

Types

Cysteinyl leukotrienes

LTC4, LTD4, LTE4 and LTF4 are often called cysteinyl leukotrienes due to the presence of the amino acid cysteine in their structure. The cysteinyl leukotrienes make up the slow-reacting substance of anaphylaxis (SRS-A). LTF4, like LTD4, is a metabolite of LTC4, but, unlike LTD4, which lacks the glutamic residue of glutathione, LTF4 lacks the glycine residue of glutathione. [10]

LTB4

LTB4 is synthesized in vivo from LTA4 by the enzyme LTA4 hydrolase. Its primary function is to recruit neutrophils to areas of tissue damage, though it also helps promote the production of inflammatory cytokines by various immune cells. Drugs that block the actions of LTB4 have shown some efficacy in slowing the progression of neutrophil-mediated diseases. [11]

LTG4

There has also been postulated the existence of LTG4, a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e.—the cysteine has been replaced by a pyruvate). Very little is known about this putative leukotriene.[ citation needed ]

LTB5

Leukotrienes originating from the omega-3 class eicosapentanoic acid (EPA) have diminished inflammatory effects. In human subjects whose diets have been supplemented with eicosapentaenoic acid, leukotrine B5, along with leukotrine B4, is produced by neutrophils. [12] LTB5 induces aggregation of rat neutrophils, chemokinesis of human polymorphonuclear neutrophils (PMN), lysosomal enzyme release from human PMN and potentiation of bradykinin-induced plasma exudation, although compared to LTB4, it has at least 30 times less potency. [13]

Biochemistry

Synthesis

Eicosanoid synthesis. (Leukotrienes at right.) Eicosanoid synthesis.svg
Eicosanoid synthesis. (Leukotrienes at right.)

Leukotrienes are synthesized in the cell from arachidonic acid by arachidonate 5-lipoxygenase. The catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone.[ citation needed ]

The lipoxygenase pathway is active in leukocytes and other immunocompetent cells, including mast cells, eosinophils, neutrophils, monocytes, and basophils. When such cells are activated, arachidonic acid is liberated from cell membrane phospholipids by phospholipase A2, and donated by the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase.[ citation needed ]

5-Lipoxygenase (5-LO) uses FLAP to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A4 (LTA4), an unstable epoxide. 5-HETE can be further metabolized to 5-oxo-ETE and 5-oxo-15-hydroxy-ETE, all of which have pro-inflammatory actions similar but not identical to those of LTB4 and mediated not by LTB4 receptors but rather by the OXE receptor (see 5-Hydroxyeicosatetraenoic acid and 5-Oxo-eicosatetraenoic acid). [14] [15]

In cells equipped with LTA hydrolase, such as neutrophils and monocytes, LTA4 is converted to the dihydroxy acid leukotriene LTB4, which is a powerful chemoattractant for neutrophils acting at BLT1 and BLT2 receptors on the plasma membrane of these cells.[ citation needed ]

In cells that express LTC4 synthase, such as mast cells and eosinophils, LTA4 is conjugated with the tripeptide glutathione to form the first of the cysteinyl-leukotrienes, LTC4. Outside the cell, LTC4 can be converted by ubiquitous enzymes to form successively LTD4 and LTE4, which retain biological activity.[ citation needed ]

The cysteinyl-leukotrienes act at their cell-surface receptors CysLT1 and CysLT2 on target cells to contract bronchial and vascular smooth muscle, to increase permeability of small blood vessels, to enhance secretion of mucus in the airway and gut, and to recruit leukocytes to sites of inflammation.[ citation needed ]

Both LTB4 and the cysteinyl-leukotrienes (LTC4, LTD4, LTE4) are partly degraded in local tissues, and ultimately become inactive metabolites in the liver.[ citation needed ]

Function

Leukotrienes act principally on a subfamily of G protein-coupled receptors. They may also act upon peroxisome proliferator-activated receptors. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions. Several leukotriene receptor antagonists such as montelukast and zafirlukast are used to treat asthma. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses. [16]

Leukotrienes are very important agents in the inflammatory response. Some such as LTB4 have a chemotactic effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. Leukotrienes also have a powerful effect in bronchoconstriction and increase vascular permeability. [17]

Leukotrienes in asthma

Leukotrienes contribute to the pathophysiology of asthma, especially in patients with aspirin-exacerbated respiratory disease (AERD), and cause or potentiate the following symptoms: [18]

Role of cysteinyl leukotrienes

Cysteinyl leukotriene receptors CYSLTR1 and CYSLTR2 are present on mast cells, eosinophil, and endothelial cells. During cysteinyl leukotriene interaction, they can stimulate proinflammatory activities such as endothelial cell adherence and chemokine production by mast cells. As well as mediating inflammation, they induce asthma and other inflammatory disorders, thereby reducing the airflow to the alveoli. The levels of cysteinyl leukotrienes, along with 8-isoprostane, have been reported to be increased in the EBC of patients with asthma, correlating with disease severity. [19] Cysteinyl leukotrienes may also play a role in adverse drug reactions in general and in contrast medium induced adverse reactions in particular. [20]

In excess, the cysteinyl leukotrienes can induce anaphylactic shock. [21]

Leukotrienes in dementia

Leukotrienes are found to play an important role in the later stages of Alzheimer's disease and related dementias in studies with animals. In tau transgenic mice, which develop tau pathology, "zileuton, a drug that inhibits leukotriene formation by blocking the 5-lipoxygenase enzyme" was found to reverse memory loss. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Eicosanoids may also act as endocrine agents to control the function of distant cells.

<span class="mw-page-title-main">Lipoxin</span> Acronym for lipoxygenase interaction product

A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.

An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor or leukotriene receptor antagonist and consequently opposes the function of these inflammatory mediators; leukotrienes are produced by the immune system and serve to promote bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and COPD. Leukotriene receptor antagonists are sometimes colloquially referred to as leukasts.

Leukotriene E<sub>4</sub> Chemical compound

Leukotriene E4 (LTE4) is a cysteinyl leukotriene involved in inflammation. It is known to be produced by several types of white blood cells, including eosinophils, mast cells, tissue macrophages, and basophils, and recently was also found to be produced by platelets adhering to neutrophils. It is formed from the sequential conversion of LTC4 to LTD4 and then to LTE4, which is the final and most stable cysteinyl leukotriene. Compared to the short half lives of LTC4 and LTD4, LTE4 is relatively stable and accumulates in breath condensation, in plasma, and in urine, making it the dominant cysteinyl leukotriene detected in biologic fluids. Therefore, measurements of LTE4, especially in the urine, are commonly monitored in clinical research studies.

Leukotriene A<sub>4</sub> Chemical compound

Leukotriene A4 (LTA4) is a leukotriene, and is the precursor for the productions of leukotriene B4 (LTB4) and leukotriene C4 (LTC4).

Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme that in humans is encoded by the ALOX5 gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms essential fatty acids (EFA) substrates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases.

Arachidonate 5-lipoxygenase inhibitors are compounds that slow or stop the action of the arachidonate 5-lipoxygenase enzyme, which is responsible for the production of inflammatory leukotrienes. The overproduction of leukotrienes is a major cause of inflammation in asthma, allergic rhinitis, and osteoarthritis.

<span class="mw-page-title-main">Cysteinyl leukotriene receptor 1</span> Protein-coding gene in humans

Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT). CYSLTR1, by binding these cysteinyl LTs contributes to mediating various allergic and hypersensitivity reactions in humans as well as models of the reactions in other animals.

<span class="mw-page-title-main">OXGR1</span> Protein-coding gene in the species Homo sapiens

2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99, is a protein that in humans is encoded by the OXGR1 gene. The Gene has recently been nominated as a receptor not only for 2-oxoglutarate but also for the three cysteinyl leukotrienes (CysLTs), particularly leukotriene E4 (LTE4) and to far lesser extents LTC4 and LTD4. Recent studies implicate GPR99 as a cellular receptor which is activated by LTE4 thereby causing these cells to contribute to mediating various allergic and hypersensitivity responses.

<span class="mw-page-title-main">Cysteinyl leukotriene receptor 2</span> Protein-coding gene in the species Homo sapiens

Cysteinyl leukotriene receptor 2, also termed CYSLTR2, is a receptor for cysteinyl leukotrienes (LT). CYSLTR2, by binding these cysteinyl LTs contributes to mediating various allergic and hypersensitivity reactions in humans. However, the first discovered receptor for these CsLTs, cysteinyl leukotriene receptor 1 (CysLTR1), appears to play the major role in mediating these reactions.

<span class="mw-page-title-main">Oxoeicosanoid receptor 1</span> Protein-coding gene in the species Homo sapiens

Oxoeicosanoid receptor 1 (OXER1) also known as G-protein coupled receptor 170 (GPR170) is a protein that in humans is encoded by the OXER1 gene located on human chromosome 2p21; it is the principal receptor for the 5-Hydroxyicosatetraenoic acid family of carboxy fatty acid metabolites derived from arachidonic acid. The receptor has also been termed hGPCR48, HGPCR48, and R527 but OXER1 is now its preferred designation. OXER1 is a G protein-coupled receptor (GPCR) that is structurally related to the hydroxy-carboxylic acid (HCA) family of G protein-coupled receptors whose three members are HCA1 (GPR81), HCA2, and HCA3 ; OXER1 has 30.3%, 30.7%, and 30.7% amino acid sequence identity with these GPCRs, respectively. It is also related to the recently defined receptor, GPR31, for the hydroxyl-carboxy fatty acid 12-HETE.

<span class="mw-page-title-main">5-Hydroxyeicosatetraenoic acid</span> Chemical compound

5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(S)-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE).

<span class="mw-page-title-main">12-Hydroxyeicosatetraenoic acid</span> Chemical compound

12-Hydroxyeicosatetraenoic acid (12-HETE) is a derivative of the 20 carbon polyunsaturated fatty acid, arachidonic acid, containing a hydroxyl residue at carbon 12 and a 5Z,8Z,10E,14Z Cis–trans isomerism configuration (Z=cis, E=trans) in its four double bonds. It was first found as a product of arachidonic acid metabolism made by human and bovine platelets through their 12S-lipoxygenase (i.e. ALOX12) enzyme(s). However, the term 12-HETE is ambiguous in that it has been used to indicate not only the initially detected "S" stereoisomer, 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE or 12S-HETE), made by platelets, but also the later detected "R" stereoisomer, 12(R)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (also termed 12(R)-HETE or 12R-HETE) made by other tissues through their 12R-lipoxygenase enzyme, ALOX12B. The two isomers, either directly or after being further metabolized, have been suggested to be involved in a variety of human physiological and pathological reactions. Unlike hormones which are secreted by cells, travel in the circulation to alter the behavior of distant cells, and thereby act as Endocrine signalling agents, these arachidonic acid metabolites act locally as Autocrine signalling and/or Paracrine signaling agents to regulate the behavior of their cells of origin or of nearby cells, respectively. In these roles, they may amplify or dampen, expand or contract cellular and tissue responses to disturbances.

<span class="mw-page-title-main">15-Hydroxyeicosatetraenoic acid</span> Chemical compound

15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(S)-HETE, and 15S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initial hydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5(S),15(S)-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE), a subset of specialized pro-resolving mediators viz., the lipoxins, a class of pro-inflammatory mediators, the eoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives.

Eoxins are proposed to be a family of proinflammatory eicosanoids. They are produced by human eosinophils, mast cells, the L1236 Reed–Sternberg cell line derived from Hodgkin's lymphoma, and certain other tissues. These cells produce the eoxins by initially metabolizing arachidonic acid, an omega-6 (ω-6) fatty acid, via any enzyme possessing 15-lipoxygenase activity. The product of this initial metabolic step, 15(S)-hydroperoxyeicosatetraenoic acid, is then converted to a series of eoxins by the same enzymes that metabolize the 5-lipoxygenase product of arachidonic acid metabolism, i.e. 5-Hydroperoxy-eicosatetraenoic acid to a series of leukotrienes. That is, the eoxins are 14,15-disubstituted analogs of the 5,6-disubstituted leukotrienes.

<span class="mw-page-title-main">Eoxin A4</span> Chemical compound

Eoxin A4, also known as 14,15-leukotriene A4, is an eoxin. Cells make eoxins by metabolizing arachidonic acid with a 15-lipoxygenase enzyme to form 15(S)-hydroperoxyeicosapentaenoic acid (i.e. 15(S)-HpETE). This product is then converted serially to eoxin A4 (i.e. EXA4), EXC4, EXD4, and EXE4 by LTC4 synthase, an unidentified gamma-glutamyltransferase, and an unidentified dipeptidase, respectively, in a pathway which appears similar if not identical to the pathway which forms leukotreines, i.e. LTA4, LTC4, LTD4, and LTE4. This pathway is schematically shown as follows:

<span class="mw-page-title-main">Eoxin D4</span> Chemical compound

Eoxin D4, also known as 14,15-leukotriene D4, is an eoxin. Cells make eoxins by metabolizing arachidonic acid with a 15-lipoxygenase enzyme to form 15(S)-hydroperoxyeicosapentaenoic acid (i.e. 15(S)-HpETE). This product is then converted serially to eoxin A4 (i.e. EXA4), EXC4, EXD4, and EXE4 by LTC4 synthase, an unidentified gamma-glutamyltransferase, and an unidentified dipeptidase, respectively, in a pathway which appears similar if not identical to the pathway which forms leukotreines, i.e. LTA4, LTC4, LTD4, and LTE4. This pathway is schematically shown as follows:

<span class="mw-page-title-main">Eoxin E4</span> Chemical compound

Eoxin E4, also known as 14,15-leukotriene E4, is an eoxin. Cells make eoxins by metabolizing arachidonic acid with a 15-lipoxygenase enzyme to form 15(S)-hydroperoxyeicosapentaenoic acid (i.e. 15(S)-HpETE). This product is then converted serially to eoxin A4 (i.e. EXA4), EXC4, EXD4, and EXE4 by LTC4 synthase, an unidentified gamma-glutamyltransferase, and an unidentified dipeptidase, respectively, in a pathway which appears similar if not identical to the pathway which forms leukotreines, i.e. LTA4, LTC4, LTD4, and LTE4. This pathway is schematically shown as follows:

<span class="mw-page-title-main">12-Hydroxyheptadecatrienoic acid</span> Chemical compound

12-Hydroxyheptadecatrienoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was discovered and structurally defined in 1973 by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg, as a product of arachidonic acid metabolism made by microsomes (i.e. endoplasmic reticulum) isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.

<span class="mw-page-title-main">5-Oxo-eicosatetraenoic acid</span> Chemical compound

5-Oxo-eicosatetraenoic acid is a nonclassic eicosanoid metabolite of arachidonic acid and the most potent naturally occurring member of the 5-HETE family of cell signaling agents. Like other cell signaling agents, 5-oxo-ETE is made by a cell and then feeds back to stimulate its parent cell and/or exits this cell to stimulate nearby cells. 5-Oxo-ETE can stimulate various cell types particularly human leukocytes but possesses its highest potency and power in stimulating the human eosinophil type of leukocyte. It is therefore suggested to be formed during and to be an important contributor to the formation and progression of eosinophil-based allergic reactions; it is also suggested that 5-oxo-ETE contributes to the development of inflammation, cancer cell growth, and other pathological and physiological events.

References

  1. ↑ Loick, H.; Theissen, J. (1994). "Die Eicosanoide als Mediatoren beim ARDS" [Eicosanoids as mediators in ARDS]. Anästhesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie (in German). 29 (1): 3–9. doi:10.1055/s-2007-996677. PMID   8142566.
  2. ↑ Salmon, John A; Higgs, Gerald A (1987). "Prostaglandins and leukotrienes as inflammatory mediators". British Medical Bulletin. 43 (2): 285–96. doi:10.1093/oxfordjournals.bmb.a072183. PMID   2825898.
  3. ↑ O'Byrne, Paul M.; Israel, Elliot; Drazen, Jeffrey M. (1997). "Antileukotrienes in the treatment of asthma". Annals of Internal Medicine. 127 (6): 472–80. doi:10.7326/0003-4819-127-6-199709150-00009. PMID   9313005. S2CID   21480605.
  4. ↑ White, Martha (1999). "Mediators of inflammation and the inflammatory process". The Journal of Allergy and Clinical Immunology. 103 (3 Pt 2): S378-81. doi: 10.1016/S0091-6749(99)70215-0 . PMID   10069896 . Retrieved 8 June 2019.
  5. ↑ Nelson, David L.; Cox, Michael M. (2008). "Leukotrienes". Lehninger Principles of Biochemistry (5th ed.). Macmillan. p.  359. ISBN   978-0-7167-7108-1.
  6. ↑ Scott JP, Peters-Golden M (September 2018). "Antileukotriene agents for the treatment of lung disease". Am. J. Respir. Crit. Care Med. 188 (5): 538–544. doi:10.1164/rccm.201301-0023PP. PMID   23822826.
  7. ↑ Feldberg, W.; Kellaway, C. H. (1938). "Liberation of histamine and formation of lysocithin-like substances by cobra venom". The Journal of Physiology. 94 (2): 187–226. doi:10.1113/jphysiol.1938.sp003674. PMC   1393616 . PMID   16995038.
  8. ↑ Feldberg, W.; Holden, H. F.; Kellaway, C. H. (1938). "The formation of lysocithin and of a muscle-stimulating substance by snake venoms". The Journal of Physiology. 94 (2): 232–48. doi:10.1113/jphysiol.1938.sp003676. PMC   1393612 . PMID   16995040.
  9. 1 2 Kellaway, C.H.; Trethewie, E.R. (1940). "The Liberation of a Slow-Reacting Smooth Muscle-Stimulating Substance in Anaphylaxis". Quarterly Journal of Experimental Physiology and Cognate Medical Sciences. 30 (2): 121–145. doi: 10.1113/expphysiol.1940.sp000825 . ISSN   1469-445X.
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  11. ↑ Crooks, S.W; Stockley, R.A (1998). "Leukotriene B4". The International Journal of Biochemistry & Cell Biology. 30 (2): 173–8. doi:10.1016/S1357-2725(97)00123-4. PMID   9608670. S2CID   45983006.
  12. ↑ von Schacky, C; Fahrer, C; Fischer, S (October 1990). "Catabolism of leukotriene B5 in humans". Journal of Lipid Research. 31 (10): 1831–1838. doi: 10.1016/S0022-2275(20)42326-0 . PMID   1964169 . Retrieved 16 January 2023.
  13. ↑ Terano, Takashi; Salmon, John A.; Moncada, Salvador (1984). "Biosynthesis and biological activity of leukotriene B5". Prostaglandins. 27 (2): 217–32. doi:10.1016/0090-6980(84)90075-3. PMID   6326200.
  14. ↑ O'Flaherty, Joseph T.; Taylor, Jennifer S.; Thomas, Michael J. (1998). "Receptors for the 5-oxo class of eicosanoids in neutrophils". The Journal of Biological Chemistry. 273 (49): 32535–41. doi: 10.1074/jbc.273.49.32535 . PMID   9829988.
  15. ↑ Powell, William S.; Rokach, Joshua (2013). "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor". Progress in Lipid Research. 52 (4): 651–65. doi:10.1016/j.plipres.2013.09.001. PMC   5710732 . PMID   24056189.
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  17. ↑ Dahlén, Sven-Erik; Björk, Jakob; Hedqvist, Per; Arfors, Karl-E.; Hammarström, Sven; Lindgren, Jan-Åke; Samuelsson, Bengt (1981). "Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response". Proceedings of the National Academy of Sciences. 78 (6): 3887–91. Bibcode:1981PNAS...78.3887D. doi: 10.1073/pnas.78.6.3887 . JSTOR   10943. PMC   319678 . PMID   6267608.
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  19. ↑ Samitas, Konstantinos; Chorianopoulos, Dimitrios; Vittorakis, Stelios; Zervas, Eleftherios; Economidou, Erasmia; Papatheodorou, George; Loukides, Stelios; Gaga, Mina (2009). "Exhaled cysteinyl-leukotrienes and 8-isoprostane in patients with asthma and their relation to clinical severity". Respiratory Medicine. 103 (5): 750–6. doi: 10.1016/j.rmed.2008.11.009 . PMID   19110408.
  20. ↑ Böhm, Ingrid; Speck, Ulrich; Schild, Hans (2005). "A possible role for cysteinyl-leukotrienes in non-ionic contrast media induced adverse reactions". European Journal of Radiology. 55 (3): 431–6. doi:10.1016/j.ejrad.2005.01.007. PMID   16129253.
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  22. ↑ "Temple researchers reverse cognitive impairments in mice with dementia". Eurekalart!. June 8, 2018.

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