# Leukotriene

Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation 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 prostaglandins, which also act as inflammatory mediators.
One of their roles (specifically, leukotriene D$_4$) 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.

## 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 glutamic residue of glutathione, LTF$_4$ lacks the glycine residue of glutathione.

### LTB$_4$

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.

### LTG$_4$

There has also been postulated the existence of LTG$_4$, a metabolite of LTE$_4$ in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e.—the cysteine has been replaced by a pyruvate).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.

### LTB$_5$

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 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 A$_4$ (LTA$_4$), 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 LTB$_4$ and mediated not by LTB$_4$ 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, LTA$_4$ is converted to the dihydroxy acid leukotriene LTB$_4$, which is a powerful chemoattractant for neutrophils acting at BLT$_1$ and BLT$_2$ receptors on the plasma membrane of these cells.
In cells that express LTC$_4$ synthase, such as mast cells and eosinophils, LTA$_4$ is conjugated with the tripeptide glutathione to form the first of the cysteinyl-leukotrienes, LTC$_4$. Outside the cell, LTC$_4$ can be converted by ubiquitous enzymes to form successively LTD$_4$ and LTE$_4$, 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 LTB$_4$ and the cysteinyl-leukotrienes (LTC$_4$, LTD$_4$, LTE$_4$) 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 LTB$_4$ 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 potentiate 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 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.
In excess, the cysteinyl leukotrienes can induce anaphylactic shock.

## Leukotrienes in dementia

Leukotrienes are found to play an important role in the later stages of Alzheimer's disease and related dementias in studies with animals. In tau transgenic mice, which develop tau pathology, "zileuton, a drug that inhibits leukotriene formation by blocking the 5-lipoxygenase enzyme" was found to reverse memory loss.