Leukotrienes are a family ofeicosanoidinflammatory mediators produced inleukocytes by theoxidation ofarachidonic acid (AA) and theessential fatty acideicosapentaenoic acid (EPA) by theenzymearachidonate 5-lipoxygenase.[1][2][3]
Leukotrienes uselipid 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 ofhistamine andprostaglandins, which also act as inflammatory mediators.[4]
One of their roles (specifically,leukotriene D4) is to trigger contractions in the smooth muscles lining the bronchioles; their overproduction is a major cause of inflammation inasthma and allergicrhinitis.[5]Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes.[6]
The nameleukotriene, introduced by Swedish biochemistBengt Samuelsson in 1979, comes from the wordsleukocyte andtriene (indicating the compound's threeconjugated 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.[7][8][9] The researchers isolated SRS from lung tissue after a prolonged period following exposure to snakevenom and histamine.[9]
LTC4,LTD4,LTE4 and LTF4 are often calledcysteinyl leukotrienes due to the presence of the amino acidcysteine in their structure. The cysteinyl leukotrienes make up theslow-reacting substance of anaphylaxis (SRS-A). LTF4, like LTD4, is a metabolite of LTC4, but, unlike LTD4, which lacks theglutamic residue ofglutathione, LTF4 lacks theglycine residue of glutathione.[10]
LTB4 is synthesizedin vivo fromLTA4 by the enzymeLTA4 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 LTB4 have shown some efficacy in slowing the progression of neutrophil-mediated diseases.[11]
There has also been postulated the existence of LTG4, a metabolite of LTE4 in which the cysteinylmoiety has been oxidized to an alpha-keto-acid (i.e.—the cysteine has been replaced by apyruvate). Very little is known about this putative leukotriene.[citation needed]
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.[12] LTB5 induces aggregation of ratneutrophils, chemokinesis of human polymorphonuclear neutrophils (PMN), lysosomal enzyme release from human PMN and potentiation of bradykinin-induced plasma exudation, although compared to LTB4, it has at least 30 times less potency.[13]
Leukotrienes are synthesized in the cell fromarachidonic acid byarachidonate 5-lipoxygenase. The catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone.[citation needed]
The lipoxygenase pathway is active in leukocytes and other immunocompetent cells, includingmast cells,eosinophils,neutrophils,monocytes, andbasophils. When such cells are activated, arachidonic acid is liberated from cell membrane phospholipids byphospholipase A2, and donated by the5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase.[citation needed]
5-Lipoxygenase (5-LO) uses FLAP to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneouslyreduces to5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it intoleukotriene A4 (LTA4), 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 LTB4 and mediated not by LTB4 receptors but rather by the OXE receptor (see5-Hydroxyeicosatetraenoic acid and5-Oxo-eicosatetraenoic acid).[14][15]
In cells equipped withLTA 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.[citation needed]
In cells that expressLTC4 synthase, such as mast cells and eosinophils, LTA4 is conjugated with the tripeptideglutathione 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 retainbiological activity.[citation needed]
The cysteinyl-leukotrienes act at their cell-surface receptorsCysLT1 andCysLT2 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.[citation needed]
Both LTB4 and the cysteinyl-leukotrienes (LTC4, LTD4, LTE4) are partly degraded in local tissues, and ultimately become inactive metabolites in the liver.[citation needed]
Leukotrienes act principally on a subfamily ofG protein-coupled receptors. They may also act uponperoxisome proliferator-activated receptors. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions. Severalleukotriene receptor antagonists such asmontelukast andzafirlukast are used to treatasthma. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses.[16]
Leukotrienes are very important agents in theinflammatory response. Some such as LTB4 have achemotactic effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. Leukotrienes also have a powerful effect inbronchoconstriction and increasevascular permeability.[17]
Leukotrienes contribute to thepathophysiology ofasthma, especially in patients withaspirin-exacerbated respiratory disease (AERD), and cause orpotentiate the followingsymptoms:[18]
Cysteinyl leukotriene receptorsCYSLTR1 andCYSLTR2 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 thealveoli. The levels of cysteinyl leukotrienes, along with8-isoprostane, have been reported to be increased in theEBC of patients withasthma, correlating with disease severity.[19] Cysteinyl leukotrienes may also play a role in adverse drug reactions in general and in contrast medium induced adverse reactions in particular.[20]
In excess, the cysteinyl leukotrienes can induceanaphylactic shock.[21]
