Leukotriene
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Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase.
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[edit] History and name
The name leukotriene, introduced by Swedish biochemist Bengt Samuelsson in 1979, comes from the words leukocyte and triene (a compound with three 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.
[edit] Biochemistry
[edit] Synthesis
Leukotrienes are synthesized in the cell from arachidonic acid by 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, 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, which converts it in two steps to leukotriene A4, an unstable epoxide. In cells equipped with LTA4 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 to inactive metabolites in the liver.
[edit] 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 (e.g. montelukast and zafirlukast) are used to treat asthma. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses [1].
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 vasoconstriction particularly of venules and of bronchoconstriction, they also increase vascular permeability. Examples of leukotrienes are LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4 .
[edit] Leukotrienes in asthma
Leukotrienes assist in the pathophysiology of asthma. Asthma is a chronic inflammatory disease which causes the following:
- airflow obstruction
- increased secretion of mucus
- mucosal accumulation
- bronchoconstriction
- infiltration of inflammatory cells in the airway wall
[edit] Cysteinyl leukotrienes
LTC4, LTD4 and LTE4 are often called cysteinyl leukotrienes due to the presence of the amino acid in their structure. Cysteinyl leukotriene receptors CysLT1 and CysLT2 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, whereby reducing the airflow to the alveoli.
[edit] Leukotriene modifiers
It has been demonstrated that leukotrienes are implicated in the inflammatory cascade leading to asthma. Leukotriene modifiers are an important therapeutic advance in managing asthma.
There are two main approaches to block the actions of leukotrienes.
- Inhibition of the 5-lipoxygenase pathway
- Antagonism of cysteinyl-leukotriene type 1 receptors
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- Agents such as montelukast and zafirlukast block the actions of cysteinyl leukotrienes at the CysLT1 receptor on target cells such as bronchial smooth muscle.
These modifiers have been shown to improve asthma symptoms, reduce asthma exacerbations and limit markers of inflammation such as eosinophil counts in the peripheral blood and bronchoalveolar lavage fluid. This demonstrates that they have anti-inflammatory properties.
[edit] See also
[edit] References
- 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. The liberation of a slow reacting smooth-muscle stimulating substance in anaphylaxis. Q J Exp Physiol 1940;30:121-145.
