They are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid.
Also by the oxidation of the essential fatty acid eicosapentaenoic by the enzyme araquidonato 5-lipoxygenase.
Leukotrienes use lipid signaling to transmit information to the cell that produces them (autocrine signaling) or neighboring cells (paracrine signaling) to regulate the immune response after infection, injury or contact with allergens .
Although its role in inflammatory processes is beneficial in helping to fight disease, higher levels of these chemicals can contribute to conditions such as asthma , arthritis and allergic reactions.
The production of leukotrienes is often accompanied by the production of histamine and prostaglandins , which also act as inflammatory mediators.
They exhibit a series of biological effects, one of their functions (specifically, leukotriene D4) is to trigger contractions in the smooth muscles that line the bronchioles.
Its overproduction is a major cause of inflammation in asthma and allergic rhinitis , stimulation of vascular permeability and attraction and activation of leukocytes.
Compared to histamine, which causes constriction of the airways and edema formation, leukotrienes are three to four orders of magnitude more powerful and the effects last longer.
Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes.
After the hydrolytic release of the phospholipids from the cell membrane, the arachidonic acid is oxygenated by a lipoxygenase in 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid.
This product is further converted to leukotrienes by removal of the hydrogen 10-pro-R and OH from the hydroperoxy group to give 5,6-oxido-7,9,11, 14-eicosatetraenoic acid (leukotriene A4).
The nucleophilic opening of the epoxide at C-6 by the sulfhydryl group of glutathione gives leukotriene C4, which is metabolized into leukotrienes D4 and E4 by sequential elimination of glutamic acid and glycine.
The last reactions are catalyzed by gamma-glutamyl transpeptidase and a particulate dipeptidase of the kidney. Alternatively, water can add to C-12 leukotriene A4, which also leads to the opening of the epoxide at C-6 with formation of 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid (leukotriene B4) .
Leucotriene B4 is metabolized by omega-hydroxylation to 20-hydroxy and 20-carboxy leukotriene B4.
Leukotrienes are also formed from eicosatrienoic acid (n-9) and eicosapentaenoic acid (n-3) after oxygenation at C-5 and eicosatrienoic acid (n-6) and arachidonic acid after oxygenation at C- 8 (eicosatrienoic acid) and C-12 or C-15 (arachidonic acid).
Although they are formed from the same and additional fatty acids such as prostaglandins and thromboxanes, the structures and reactions involved in the biosynthesis and catabolism of the leukotrienes are completely separate from those required for the formation and metabolism of prostaglandins.
Leukotrienes appear to provide a new system of biological regulators that are important in many diseases that involve inflammatory or immediate hypersensitivity reactions.
History and name of leukotrienes
Leukotrienes were discovered in 1938 and 1940 by Feldberg and Kellaway as a contraction factor of smooth muscle in pulmonary perfusates. It was called “slow reaction substance” (SRS) or “slow reaction substance of anaphylaxis” (SRS-A) until 1979, when its structure was reported.
The term “leukotriene” was introduced at that time as a trivial name for the new type of compound. Leukotrienes C4 and D4 are conjugates of glutathione and cysteinylglycine, respectively, of arachidonic acid.
The name leukotriene, introduced by the Swedish biochemist Bengt Samuelsson in 1979, comes from the words leukocyte and triene (indicating the three conjugated double bonds of the compound).
The researchers isolated the slow substance that stimulates the smooth muscle of the lung tissue after a prolonged period after exposure to snake venom and histamine. Leukotrienes are commercially available to the research community.
LTC4, LTD4, LTE4 and LTF4 are often called cysteinyl leukotrienes due to the presence of the amino acid cysteine in their structure.
Cysteinyl leukotrienes constitute the slow-reacting substance of anaphylaxis (SRS-A). LTF4, like LTD4, is a metabolite of LTC4, but, unlike LTD4, which lacks the glutathione glutathione residue, LTF4 lacks the glycine glycine residue.
LTB4 is synthesized in vivo from LTA4 by the enzyme LTA4 hydrolase. Its main function is to recruit neutrophils to areas of tissue damage, although it also helps to promote the production of inflammatory cytokines by several immune cells.
Drugs that block the actions of LTB4 have shown some efficacy in slowing the progression of neutrophil-mediated diseases.
Leukotriene B4 promotes the migration of white blood cells:
Leukotriene B4 recruits white blood cells (neutrophils, CD4 + T cells and CD8 + T cells) at sites of inflammation and injury by binding to its receptor (BLT1) in these cells.
In response to infections and allergic reactions, immune cells (mast cells) release leukotrienes, which attract white blood cells (neutrophils and CD8 + T cells) to the affected areas.
Leukotriene B4 increases antimicrobial defense:
In human leukocytes, leukotriene B4 stimulates the production of molecules with potent antimicrobial effects (eg, α-defensins).
In addition to eliminating bacteria and viruses, these molecules also increase the production of leukotriene B4.
In influenza A virus, leukotriene B4 significantly reduced the amount of virus in the lung by stimulating the release of antimicrobial proteins.
Similarly, in one study (DB-RCT) of 23 healthy individuals, spray application of leukotriene B4 in the nose increased the production of myeloperoxidase (MPO) and other antimicrobial proteins after 4 hours.
In addition, in cell-based studies, white blood cells (neutrophils) activated by leukotriene B4 killed several viruses.
However, in another study (DB-RCT), leukotriene B4 failed to reduce the incidence of the common cold and its symptoms in 18 healthy subjects infected with the HRV-16 virus after 6 days.
Leukotriene B4 can also improve phagocytosis, or the absorption of bacteria and other microorganisms causing diseases by white blood cells (eg, macrophages). It does so by joining its receptor in these cells and activating the cellular signals that initiate the process.
In turn, activated immune cells attract more cells that produce leukotriene B4, which results in more activated immune cells.
Leukotriene B4 also suppresses the action of another fatty messenger (PGE2) in blocking phagocytosis.
Leukotriene B4 determines the duration of inflammatory responses:
PPARα is a protein that promotes the production of enzymes involved in the breakdown of fatty acids and their derivatives, such as leukotriene B4.
Because leukotriene B4 activates PPARα, its interaction with this protein controls the inflammatory response by reducing its duration.
Leukotriene B4 activates the immune response:
Leukotriene B4 binds to its receptor (BLT1) in dendritic cells (white blood cells that capture and digest foreign substances). This leads to an increase in the production of IL-12, which is required for the development of Th1 immunity.
It 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 (ie, cysteine has been replaced by a pyruvate). Very little is known about this putative leukotriene.
Leukotrienes that originate from eicosapentaenoic acid of the omega-3 (EPA) class have decreased inflammatory effects.
LTB5 induces aggregation of rat neutrophils, human polymorphonuclear chemokinesis, release of human polymorphonuclear lysosomal enzymes and enhancement of plasma exudation induced by bradykinin, although compared to LTB4, it has at least 30 times less potency.
Synthesis of leukotrienes
Leukotrienes are synthesized in the cell from arachidonic acid by the 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, phospholipase A2 releases arachidonic acid from the phospholipids of the cell membrane and the 5-lipoxygenase activating protein (FLAP) donates it to 5-lipoxygenase.
5-HETE can be further metabolized to 5-oxo-TEE and 5-oxo-15-hydroxy-TEE, all of which have proinflammatory actions similar but not identical to those of LTB4 and not mediated by LTB4 receptors, but rather by the OXE Receiver.
Function of leukotrienes
Leukotrienes act mainly in a subfamily of G-protein coupled receptors. Leukotrienes are involved in allergic and asthmatic reactions and act to maintain inflammatory reactions.
Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric diseases. Some, such as LTB4, have a chemotactic effect on the migration of neutrophils, and as such they help carry the necessary cells to the tissue.
Leukotrienes in asthma
Leukotrienes contribute to the pathophysiology of asthma, especially in patients with respiratory disease exacerbated with aspirin (AERD), and cause or potentiate the following symptoms:
- Obstruction of air flow.
- Increased mucus secretion.
- Mucosal accumulation.
- Infiltration of inflammatory cells in the wall of the respiratory tract.
How do leukotrienes work in asthma?
Acute asthma attacks are often triggered by allergens or exercise. Inflammatory molecules called leukotrienes are one of several substances that are released by mast cells during an asthma attack , and leukotrienes are the main responsible for bronchoconstriction.
In the more severe chronic cases of asthma, general bronchial hyperreactivity (or smooth muscle contractions) is caused largely by eosinophils, which are attracted to the bronchioles by leukotrienes (and other chemo-attractants) and which in turn they also produce leukotrienes.
Therefore, leukotrienes appear to be critical both for triggering acute asthma attacks and for causing longer-term hypersensitivity of the airways in chronic asthma.
Leukotrienes are derived from arachidonic acid, the precursor of prostaglandins. There are two families of leukotrienes. The first group acts mainly under conditions in which inflammation depends on neutrophils, such as cystic fibrosis, inflammatory bowel disease and psoriasis.
The second group (cysteinyl-leukotrienes) refers mainly to the bronchoconstriction induced by eosinophils and mast cells in asthma. They bind to highly selective receptors in the bronchial smooth muscle and other tissues of the respiratory tract.
Drugs that can interfere with the activity of leukotrienes have been designed.
It has recently been shown that both inhibitors of leukotriene synthesis and cysteinyl-leukotriene receptor antagonists protect asthmatic patients from asthma attacks, but are not useful as “rescue remedies” once the attack has already has started.
They act by preventing the release of leukotrienes from mast cells and eosinophils or by blocking the specific leukotriene receptors in the bronchial tissues, thus preventing bronchoconstriction, mucus secretion and edema.
These medications also reduce the influx of eosinophils, which limits inflammatory damage in the airways. These oral, non-steroidal, anti-inflammatory medications reduce the incidence of acute asthma attacks when taken regularly.
Role of cysteinyl leukotrienes
It has been reported that the levels of cysteinyl leukotrienes, together with 8-isoprostane, increase in the exhaled breath condensate of patients with asthma, which correlates with the severity of the disease.
Cysteinyl leukotrienes may also play a role in adverse reactions to medications in general and, in contrast, in adverse reactions induced by the media in particular.
Cysteinyl leukotrienes (leukotrienes C4, D4 and E4) are mainly known for their powerful ability to narrow the airways, increase mucus production and promote swelling and inflammation in the lungs, which worsens asthma symptoms.
Cysteinyl leukotrienes recruit white blood cells:
Inhalation of leukotriene E4 increases the amount of white blood cells (eosinophils and neutrophils) in the mucous lining of the airways after 4 hours in patients with asthma.
In a cell-based study, the cytokines IL-4 and IL-13 increased the production of cysteinyl leukotriene receptors (CysLT1) in human monocytes and lung macrophages (white blood cells that capture and “eat” foreign and harmful substances).
The receptors for cysteinyl leukotrienes are also highly concentrated in the white blood cells (eosinophils and mast cells) of the nasal tissues of patients with hay fever and inflammation of the nose.
Likewise, the production of cysteinyl leukotriene receptors (CysLT1) increases in the white blood cells of subjects with chronic inflammation of the nose sensitive to aspirin (rhinosinusitis).
Cysteinyl leukotrienes activate the production of cytokines:
Leukotrienes D4 and E4 trigger the release of IL-4 by eosinophils (white blood cells that fight viral and parasitic infections and cause allergic symptoms). The molecules that block the cysteinyl receptors (CysLT1) prevent the production of this cytokine.
Mast cells (white blood cells involved in allergic reactions) also release several cytokines, including IL-5 and TNF-α in response to stimulation with leukotrienes C4 and E4.
Cysteinyl leukotrienes are required for the functioning and function of the immune cell:
Leukotrienes C4 and D4 restored the migration of dendritic cells, white blood cells that sequester foreign substances, in mice lacking a protein that transports leukotriene C4 outside the cell after its synthesis.
In a mouse model with asthma, cysteinyl leukotrienes triggered a Th2 response in the lungs by increasing the production of IL-5 from dendritic cells.
Cysteinyl leukotrienes promote the loss of blood vessels:
In mice deficient in the enzyme that produces cysteinyl leukotrienes (LTC4S) or receptors for cysteinyl leukotrienes (CysLT1), the leakage of blood vessels was reduced by 50%. These results indicate the participation of cysteinyl leukotrienes in the increase in blood vessel loss.
Other functions of leukotrienes:
Leukotrienes improve the formation of white blood cells:
By binding to the cysteinyl leukotriene (CysLT1) receptors in blood and bone marrow cells, leukotriene D4 stimulates the formation of eosinophils (white blood cells involved in parasitic and allergic reactions).
The addition of leukotrienes B4, C4 and D4 to bone marrow cells previously treated with blockers of leukotriene production restored the formation of several types of white blood cells.
Cysteinyl leukotrienes can also suppress the inhibition of the production of white blood cells (eosinophils) by other inflammatory molecules (prostaglandin E2).
Leukotrienes promote bone loss:
The bone mass is maintained by a balance between bone formation and bone loss. During bone loss, cells called osteoclasts break down bone tissue and release its minerals, including calcium, into the blood.
In cell-based studies, the addition of leukotrienes B4 and D4 to osteoclasts improved the bone loss activity of these cells.
In addition, leukotriene B4 promotes the production of functional osteoclasts in human white blood cells.
Leukotrienes of all types also participated in the recruitment and production of osteoclasts during bone loss activity.
Leukotrienes and allergies:
Patients with hay fever (allergic rhinitis) show increased levels of all types of leukotrienes in the nose and breathing.
In addition, the white blood cells of patients with asthma produce more leukotrienes B4 and C4 than those of healthy individuals.
In addition, drugs that inhibit the enzyme that produces leukotrienes (5-LOX) in patients with seasonal allergies reduce symptoms and levels of leukotriene B4.
Patients with chronic sinus infections also respond favorably to drugs that block cysteinyl leukotriene receptors.
Both types of leukotrienes are involved in the development of eczema. Leukotriene B4 recruits inflammatory cells in the skin (neutrophils, eosinophils and Th2 cells), while cysteinyl leukotrienes cause scars on the skin.
In addition, high levels of leukotriene B4 and C4 are found in skin lesions of patients with eczema.
Leukotriene B4 also causes white blood cells to migrate to the mucous lining of the outer eye. This may explain in part why leukotriene B4 levels are higher in the tears of patients with seasonal allergic pink eyes.
Treatments for allergic conjunctivitis include:
- The combination of histamine H1 receptor blockers and drugs that block the enzymes that produce leukotriene B4.
- Leucotriene B4 leucotriene receptor blockers and cysteinil.
In anaphylaxis , a life-threatening allergic reaction that occurs after exposure to an allergen, the increased loss of blood vessels is essential, as it improves the transport of molecules that promote the reaction (leukotrienes, prostaglandins, histamine).
Leukotrienes and heart diseases:
Leukotriene B4 is produced in plaques (accumulation of cholesterol, fat and calcium) within the arteries. In addition, patients with heart disease have higher levels of leukotriene E4 in the urine.
In addition, deficiencies in the enzymes involved in the production of leukotrienes, as well as treatment with drugs that block these enzymes, prevent hardening of the arteries.
The production of all enzymes involved in the leukotriene pathway increases in cells located in the arterial walls of patients with hardening of the arteries.
Both the deletion of the leukotriene B4 receptor (BLT1) and the treatment with a drug that blocks this receptor prevented the early development of an aneurysm.
The production of cysteinyl leukotrienes is greater in the wall of stomach aortic aneurysms (enlargement of the aorta of the stomach). This causes the release of enzymes involved in the development and rupture of aneurysms.
Similarly, elevated levels of cysteinyl leukotrienes have been observed in patients after cerebral ischemia.
High levels of cysteinyl leukotrienes were found in newborns with high blood pressure in the lungs. A poor clinical outcome after diagnosis was related to high levels of leukotrienes B4, C4 and E4.
In patients with aortic valve stenosis, the production of leukotrienes is activated. Its inflammatory function increases the severity of this disease.
Leukotrienes and chronic obstructive pulmonary disease (COPD):
Leukotriene B4 is higher in exhaled breath samples from patients with chronic obstructive pulmonary disease than in healthy people.
The recruitment of white blood cells in the airways increases during the progression of chronic obstructive pulmonary disease and decreases during recovery.
Leukotrienes and metabolic disorders:
Treatments with insulin synthesis blockers or leukotrienes restored levels of leukotriene B4, thus reducing inflammation.
Leukotriene B4 levels are elevated in the adipose tissue, where they trigger the production of cytokines and worsen inflammation. The binding of leukotriene B4 to its receptor promotes insulin resistance.
Although its products, leukotrienes B4 and D4 can cause the death of liver cells, 5-LOX also plays a role in the maintenance of pancreatic function.
Leukotrienes and Cancer:
Leukotriene B4 levels increase in prostate cancer and human colon tissues. In addition, the production of its receptor is higher in human pancreatic tumors.
In cell-based studies, high levels of leukotriene D4 led to an increase in the production of COX2 in the colon, which promotes colon cancer.
The cysteinyl leukotriene receptors (CysLT1) are also very abundant in prostate and colon cancer. The highest concentrations are linked to poor survival.
In addition, leukotrienes of both types improve the survival, adherence and migration of colon cancer cells.
However, cysteinyl leukotrienes have opposite effects in colorectal cancer. Depending on the receptor to which they are attached, they can promote (CysLT1) or reduce (CysLT2) the reproduction of cancer cells.
Leukotrienes and rheumatoid arthritis:
Leukotriene B4 promotes the adherence of inflammatory white blood cells (neutrophils) to the walls of blood vessels, which promotes the development of rheumatoid arthritis by activating the inflammatory response.
In addition, the production of leukotriene B4 receptors increases in tissues and joint cells of patients with rheumatoid arthritis . The severity of this disease is reduced with a treatment that blocks these receptors.
The elimination of a protein that activates the enzyme responsible for the production of leukotrienes (5-LOX) reduced the severity of rheumatoid arthritis by 73% and its incidence by 23%.
Similarly, the presence of functional enzymes that produce leukotriene B4 is required for mice to develop the disease.
Leukotrienes and neurodegenerative diseases:
By activating the NF-kB pathway, leukotriene D4 increases the enzymes that produce amyloid-β, which increases the risk of Alzheimer’s disease.
The elimination of the enzyme required for the production of leukotrienes (5-LOX) slows the progression of Alzheimer’s.
Interestingly, patients with Alzheimer’s disease show higher production of this enzyme and levels of leukotriene B4 compared to healthy individuals.
Similarly, in brain cells treated with a neurotoxin, the production of an enzyme that initiates the synthesis of leukotrienes (5-LOX) and leukotriene B4 increased, causing the death of brain cells. The addition of a blocker of this enzyme promoted the survival of these brain cells.
Leukotrienes and stomach pain:
In patients with familial Mediterranean fever (FMF), an inflammatory disorder that causes stomach pain, leukotriene B4 urine levels are higher than those of healthy individuals.
In addition, high concentrations of leukotrienes B4, C4 and D4 are found in the stomach juices of children infected with Helicobacter pylori, causing stomach pain.
In 5 children suffering from food allergies, blocking leukotriene receptors with medication (montelukast sodium) prevented stomach pain during one year of oral immunotherapy.
This strategy also relieves symptoms of stomach pain in other inflammatory diseases such as Henoch-Schönlein purpura, mastocytosis and eosinophilic gastroenteritis.
In contrast, stomach pain was the most common non-psychiatric side effect observed in children with asthma or early wheezing treated with leukotriene receptor blockers.
Leukotrienes and sensitivity to pain:
After nerve injury, the levels of leukotriene B4 and its receptor (BLT1) are highest in spinal nerve cells. This improves the activity of the receptors involved in pain (NMDA) and, ultimately, increases sensitivity to pain.
Similarly, the binding of leukotriene B4 to its receptor enhances the activity of the receptors involved in inflammatory pain, TRPV1.
While low concentrations of this leukotriene trigger this process, higher concentrations allow leukotriene B4 to bind with another receptor (BLT2), which leads to an opposite effect.