Leukotrienes are a family of eicosanoid inflammation produced in by the redox of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.
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 , 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.
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.
Types
Cysteinyl leukotrienes
LTC
4, LTD
4, LTE
4 and LTF
4 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). LTF
4, like LTD
4, is a metabolite of LTC
4, but, unlike LTD
4, which lacks the
glutamate residue of
glutathione, LTF
4 lacks the
glycine residue of glutathione.
[ internet checked April 24, 2012]
LTB4
LTB
4 is synthesized
in vivo from LTA
4 by the enzyme LTA
4 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 LTB
4 have shown some efficacy in slowing the progression of neutrophil-mediated diseases.
LTG4
There has also been postulated the existence of LTG
4, a metabolite of LTE
4 in which the cysteinyl
functional group has been oxidized to an alpha-keto-acid (i.e.—the cysteine has been replaced by a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.
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.
LTB
5 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 LTB
4, it has at least 30 times less potency.
Biochemistry
Synthesis
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 , , , , and . 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 redox 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).
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 inflammation 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
Potentiator the following
:
-
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
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 Anaphylaxis.
See also
-
A chemical synthesis of Leukotriene A methyl ester
-
(14,15-leukotrienes)
Further reading
-
Bailey, J. Martyn (1985) Prostaglandins, leukotrienes, and lipoxins: biochemistry, mechanism of action, and clinical applications Plenum Press, New York,
-
Lipkowitz, Myron A. and Navarra, Tova (2001) The Encyclopedia of Allergies (2nd ed.) Facts on File, New York, p. 167,
-
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,
External links
