Leukotriene



Leukotrienes are fatty signaling molecules. They were first found in leukocytes (hence their name). One of their roles (specifically, leukotriene D4) is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis. Leukotriene antagonists are used to treat these diseases by inhibiting the production or activity of leukotrienes.

Leukotrienes are naturally produced eicosanoid lipid mediators. Leukotrienes use both autocrine signalling and paracrine signalling to regulate the body's response. Leukotrienes are produced in the body from arachidonic acid by the enzyme 5-lipoxygenase. Their production usually accompanies the production of histamine.

Leukotrienes produced within a cell convey signals that act either on the cell producing them (autocrine signalling) or on neighboring cells (paracrine signalling) to regulate the immune response.

Types
Examples of leukotrienes are LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4.

LTC4, LTD4 and LTE4 are often called cysteinyl leukotrienes due to the presence of the amino acid cysteine in their structure. Together, the cysteinyl leukotrienes make up the slow-reacting substance of anaphylaxis (SRS-A).

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a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e., the cysteine has been replaced by a pyruvate).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.

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.

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.

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.

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 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 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
Leukotrienes contribute to the pathophysiology of asthma, causing or potentiating the following symptoms:
 * airflow obstruction
 * increased secretion of mucus
 * mucosal accumulation
 * bronchoconstriction
 * infiltration of inflammatory cells in the airway wall

Role of cysteinyl leukotrienes
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, thereby reducing the airflow to the alveoli.

In excess, the cysteinyl leukotrienes can induce anaphylactic shock.

Leukotriene modifiers

 * See leukotriene antagonist