leukotrienes

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/24 18:08:39」(JST)

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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.

LTB₄

LTC₄ is a cysteinyl leukotriene, as are D4 and E4.

LTD₄

LTE₄

Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid by the enzyme arachidonate 5-lipoxygenase. As their name implies, leukotrienes were first discovered in leukocytes, but have since been found in other immune cells.

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. Leukotriene production is usually accompanied by the production of histamine and prostaglandins, which also act as inflammatory mediators.

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. Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes.

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. The researchers isolated SRS from lung tissue after a prolonged period following exposure to snake venom and histamine.

Leukotrienes are commercially available to the research community.

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.

LTB₄

Main article: Leukotriene B4

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.

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.

Biochemistry

Synthesis

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.

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.

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 metabolizze 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-Hydroxyicosatetraenoic acid and 5-oxo-eicosatetraenoic acid).

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.

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.

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.

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

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.

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.

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:

• airflow obstruction
• increased secretion of mucus
• mucosal accumulation
• bronchoconstriction
• infiltration of inflammatory cells in the airway wall

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. Cysteinyl leukotrienes may also play a role in adverse drug reactions in general and in contrast medium induced adverse reactions in particular.

In excess, the cysteinyl leukotrienes can induce anaphylactic shock.

See also

• A chemical synthesis of Leukotriene A methyl ester
• Eoxins (14,15-leukotrienes)

References

• Lipkowitz, Myron A. and Navarra, Tova (2001) The Encyclopedia of Allergies (2nd ed.) Facts on File, New York, p. 167, ISBN 0-8160-4404-X
• Samuelsson, Bengt (ed.) (2001) Advances in prostaglandin and leukotriene research: basic science and new clinical applications: 11th International Conference on Advances in Prostaglandin and Leukotriene Research: Basic Science and New Clinical Applications, Florence, Italy, June 4–8, 2000 Kluwer Academic Publishers, Dordrecht, ISBN 1-4020-0146-0
• Bailey, J. Martyn (1985) Prostaglandins, leukotrienes, and lipoxins: biochemistry, mechanism of action, and clinical applications Plenum Press, New York, ISBN 0-306-41980-7

External links

• Leukotrienes at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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• 1. 喘息の治療において5-リポキシゲナーゼ経路に影響する薬剤 agents affecting the 5 lipoxygenase pathway in the treatment of asthma
• 2. Mast cell-derived mediators
• 3. 好酸球の生物学および好酸球増多症の原因 eosinophil biology and causes of eosinophilia
• 4. 12歳未満の小児における慢性喘息：持続性喘息の治療およびコントロール薬 asthma in children younger than 12 years treatment of persistent asthma with controller medications
• 5. アスピリンによる呼吸器疾患の増悪 aspirin exacerbated respiratory disease

English Journal

• An update on the management of aspirin-exacerbated respiratory disease.

• Lee JH1, Jung CG2, Park HS1.
• Expert review of respiratory medicine.Expert Rev Respir Med.2018 Feb;12(2):137-143. doi: 10.1080/17476348.2018.1417843. Epub 2017 Dec 18.
• PMID 29249187

• Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages.

• Ringleb J1, Strack E1, Angioni C2, Geisslinger G2, Steinhilber D3, Weigert A1, Brüne B4.
• Journal of immunology (Baltimore, Md. : 1950).J Immunol.2018 Jan 15;200(2):857-868. doi: 10.4049/jimmunol.1700609. Epub 2017 Dec 11.
• PMID 29229677

• Defining murine organogenesis at single-cell resolution reveals a role for the leukotriene pathway in regulating blood progenitor formation.

• Ibarra-Soria X1, Jawaid W2,3,4, Pijuan-Sala B2,3, Ladopoulos V2,3, Scialdone A5,6,7, Jörg DJ8,9, Tyser RCV10, Calero-Nieto FJ2,3, Mulas C3, Nichols J3, Vallier L6,11,12, Srinivas S10, Simons BD3,8,9, Göttgens B13,14, Marioni JC15,16,17.
• Nature cell biology.Nat Cell Biol.2018 Jan 8. doi: 10.1038/s41556-017-0013-z. [Epub ahead of print]
• PMID 29311656

Japanese Journal

• 脂質を基軸とした免疫調節

• YAKUGAKU ZASSHI 137(5), 503-515, 2017
• NAID 130005631393

• Diagnostic utility of fractional exhaled nitric oxide in prolonged and chronic cough according to atopic status

• Allergology International 66(2), 344-350, 2017
• NAID 130005628255

• 気道アレルギー炎症におけるcysteinyl leukotriene 2受容体の役割 (特集 免疫機能を制御するサイトカインや受容体の新展開)

• 臨床免疫・アレルギー科 = Clinical immunology & allergology 66(6), 555-559, 2016-12
• NAID 40021030381

Related Links

• Leukotriene Modifiers and Allergies - WebMD - Better ...

Leukotriene modifiers (leukotriene antagonists) are medicines used to manage allergic rhinitis or allergies, as well as prevent asthma. These novel drugs work by blocking the action of leukotrienes. They are typically not ...

• Leukotriene | definition of leukotriene by Medical dictionary

Leukotriene modifiers: Leukotrienes are potent broncho-constrictors and antileukotriene drugs are either receptor antagonists or enzyme inhibitors. Asthma in children management issues for family doctors Leukotrienes have been ...

• Leukotrienes | definition of leukotrienes by Medical dictionary

Products of eicosanoid metabolism (usually, arachidonate) with several physiologic roles, such as mediation of inflammation and participation in allergic reactions; leukotrienes differ from the related prostaglandins and thromboxanes ...

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