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.
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 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.
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LTG4, a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e.—the cysteine has been replaced by a pyruvate).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.
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.
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
- airflow obstruction
- increased secretion of mucus
- mucosal accumulation
- 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.
- A chemical synthesis of Leukotriene A methyl ester
- Eoxins (14,15-leukotrienes)
- Salmon, JA; Higgs, GA (April 1987). "Prostaglandins and leukotrienes as inflammatory mediators.". British medical bulletin 43 (2): 285–96. PMID 2825898. Retrieved 3 December 2012.
- O'Byrne, Paul; Elliot Israel (September 1997). "Antileukotrienes in the Treatment of Asthma". Annals of Internal Medicine 127 (6): 472–480. doi:10.7326/0003-4819-127-6-199709150-00009. Retrieved 3 December 2012.
- David L. Nelson, Michael M. Cox. Lehninger's Principles of Biochemistry, Fifth Edition. W.H. Freeman and Co., 2008, p. 359.
- Feldberg W, Kellaway CH. Liberation of histamine and formation of lyscithin-like substances by cobra venom. J Physiol 1938;94:187-226.
- Feldberg W, Holden HF, Kellaway CH. The formation of lyscithin and of a muscle-stimulating substance by snake venoms. J Physiol 1938;94:232-248.
- Kellaway CH, Trethewie ER. (April 1, 1940). "The liberation of a slow reacting smooth-muscle stimulating substance in anaphylaxis" (pdf). Q J Exp Physiol 30 (2): 121–145.
- internet checked April 24, 2012
- Crooks, S.W; Stockley, R.A (March 1998). "Leukotriene B4". The International Journal of Biochemistry & Cell Biology 30 (2): 173–178. doi:10.1016/S1357-2725(97)00123-4.
- J. Biol. Chem. 273 (49): 32535–32441. Dec 1998
- Prog Lipid Res. 2013 Oct;52(4):651-65. doi: 10.1016/j
- Manev R, Manev H (2004). "5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders". Crit Rev Neurobiol 16 (1–2): 181–6. doi:10.1615/CritRevNeurobiol.v16.i12.190. PMID 15581413.
- Dahlen, Sven-Erik; Bjork, Jakob; Hedqvist, P; Arfors, KE; Hammarström, S; Lindgren, JA; Samuelsson, B (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 of the United States of America 78 (6): 3887–3891. doi:10.1073/pnas.78.6.3887. JSTOR 10943. PMC 319678. PMID 6267608.
- Berger, Abi (10 July 1999). "Science commentary: What are leukotrienes and how do they work in asthma?". BMJ 319 (90): 90–90. doi:10.1136/bmj.319.7202.90.
- Samitas K, Chorianopoulos D, Vittorakis S, Zervas E, Economidou E, Papatheodorou G, Loukides S, Gaga M (May 2009). "Exhaled cysteinyl-leukotrienes and 8-isoprostane in patients with asthma and their relation to clinical severity.". Respir Med. 103 (5): 750–6. doi:10.1016/j.rmed.2008.11.009. PMID 19110408.
- Böhm I et al. A possible role for cysteinyl-leukotrienes in non-ionic contrast media induced adverse reactions. Eur J Radiol 2005; 55: 431 - 436
- Brocklehurst, WE (1960). "The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock". J Physiol 151 (3): 416–35. PMC 1363273. PMID 13804592.
- 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