Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase. Autocrine signaling is a form of signalling in which a cell secretes a chemical messenger (called the autocrine agent) that signals the same cell. ... Paracrine signalling is a form of signalling in which the target cell is close to the signal releasing cell, and the signal chemical is broken down too quickly to be carried to other parts of the body. ... In biochemistry, eicosanoids are a class of oxygenated hydrophobic cytokines that largely function as a autocrine and paracrine mediators. ... Arachidonic acid is a polyunsaturated fatty acid with twenty carbons and four cis double bonds, the first at the omega-6 position (20:4n-6). ...

History and name

The name leukotriene 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. White Blood Cells is also the name of a White Stripes album. ... Histamine is a hemolytic protein involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. ...

Biochemistry

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. Arachidonic acid is a polyunsaturated fatty acid with twenty carbons and four cis double bonds, the first at the omega-6 position (20:4n-6). ... Lipoxygenases are a class of enzymes which add oxygen to lipids. ... General Name, Symbol, Number oxygen, O, 8 Chemical series Nonmetals Group, Period, Block 16, 2, p Appearance colorless Atomic mass 15. ... Arachidonic acid is a polyunsaturated fatty acid with twenty carbons and four cis double bonds, the first at the omega-6 position (20:4n-6). ... White Blood Cells is also the name of a White Stripes album. ... 5-lipoxygenase activating protein, or FLAP, is a protein necessary for the activation of 5-lipoxygenase and therefor the production of leukotrienes. ...

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 antagonists are used to treat asthma. Recent research points to a role of 5-lipoxygenase in cardiovacular and neuropsychiatric illnesses [1]. In cell biology, G-protein-coupled receptors, also known as GPCR, seven transmembrane receptors, heptahelical receptors, or 7TM receptors, are a class of transmembrane receptors. ... PPAR gamma In cell biology, peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor isoforms that exist across biology. ...

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.

Leukotrienes in asthma

Leukotrienes assist in the pathophysiology of asthma. Asthma is a chronic inflammatory disease which causes the following: Pathophysiology is the study of the disturbance of normal mechanical, physical, and biochemical functions that a disease causes. ...

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

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, whereby reducing the airflow to the alveoli. A mast cell (or mastocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. ... Eosinophils are white blood cells that are responsible for combating infection by parasites in the body. ... A mast cell (or mastocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ...

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

Drugs such as zileuton block 5-lipoxygenase, inhibiting the synthetic pathway of leukotriene metabolism.

• Anatgonism of cysteinyl-leukotriene type 1 receptors

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.

See also

• A chemical synthesis of Leukotriene A methyl ester

The Wittig reaction is a chemical reaction of an aldehyde or ketone with a phosphonium ylide to give an alkene and triphenylphosphine oxide. ...

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.