Leukotriene

$Insertformulahere$ Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase.

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 in 1938 by Feldberg and Kellaway. The researchers isolated SRS from lung tissue after a prolonged period following exposure to snake venom and histamine.

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 and in macrophages and synthesizes leukotrines.

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.

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

Asthma is a chronic inflammatory disease causing airflow obstruction. Leukotrienes assist in the pathophysiology of asthma causing:

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.

Leukotriene modifiers

It has been demonstrated that leukotrienes is implicated in the inflammatory cascade leading to asthma. Leukotrienes modifiers are an important therapeutic advancement in managing asthma.

There are 2 main mechanisms of action by leukotriene modifiers:

Inhibition of 5-lipoxygenase pathway

This is whereby blocking the enzyme 5-lipoxygenase, inhibiting the lipoxygenase pathway of arachidonic acid metabolism.

Cysteinyl leukotriene receptor antagonism

Agents block actions of cysteinyl leukotrienes on target cells such as epithelial cells.

These modifiers have shown to reduce eosinophil cell counts in the peripheral blood and bronchoalycolar lavage fluid. This demonstrates that they have anti-inflammatory properties. Bronchodilation is also observed.