Leukotriene

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Leukotrienes
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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

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]

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 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

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

glutamic residue of glutathione, LTF4 lacks the glycine residue of glutathione.[10]

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.[11]

LTG4

There has also been postulated the existence of LTG4, a metabolite of LTE4 in which the cysteinyl

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.

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.)

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-

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

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

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

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

symptoms:[18]

  • Airflow obstruction
  • Increased secretion of mucus
  • Mucosal accumulation
  • Bronchoconstriction
  • Infiltration of inflammatory cells in the airway wall

Role of cysteinyl leukotrienes

Cysteinyl leukotriene receptors

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

memory loss.[22]

See also

References

  1. PMID 8142566
    .
  2. PMID 2825898
    .
  3. 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.
    PMID 10069896
    . Retrieved 8 June 2019.
  5. ISBN 978-0-7167-7108-1
    .
  6. PMID 23822826
    .
  7. PMID 16995038
    .
  8. PMID 16995040
    .
  9. ^
    ISSN 1469-445X
    .
  10. ^ internet checked April 24, 2012[full citation needed]
  11. S2CID 45983006
    .
  12. PMID 1964169
    . Retrieved 16 January 2023.
  13. PMID 6326200
    .
  14. PMID 9829988
    .
  15. PMID 24056189
    .
  16. PMID 15581413
    .
  17. PMID 6267608
    .
  18. PMID 10398630
    .
  19. PMID 19110408
    .
  20. PMID 16129253
    .
  21. PMID 13804592
    .
  22. ^ "Temple researchers reverse cognitive impairments in mice with dementia". Eurekalart!. June 8, 2018.

Further reading

External links
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