Leukotrienes
According to the study of Prostaglandins and leukotrienes as inflammatory mediators by John A Salmon and Gerald A Higgs(a), Leukotrienes
is produced in leukocytes as a result of oxidative metabolism of
arachidonic acid by the enzyme arachidonate 5-lipoxygenase, belonging to
the family of eicosanoid inflammatory mediators(a). Its production is
usually accompanied by the production of histamine and prostaglandins.
1. Leukotrienes in immunopathogenesis of rheumatoid arthritis
Leukotrienes are a family of paracrine
agents derived from oxidative metabolism of arachidonic acid. According
to the study by the Tehran University of Medical Sciences, Leukotrienes (often leukotriene B4)
as potent chemotactic agents can provoke most signs and symptoms in
rheumatoid arthritis by initiating, coordinating, sustaining, and
amplifying the inflammatory response,
through recruitment of leukocytes. A number of studies have reported
that pharmacological modulation in this field can significantly
attenuate clinical manifestations associated with different inflammatory pathologies(1).
2. Leukotrienes and inflammatory and allergic response
According to the study to Department of Medical Biochemistry and Biophysics, Karolinska Institutet,
Leukotrienes are recognized as important
signal molecules in a variety of inflammatory
and allergic conditions affecting the skin, joints, gastrointestinal
and respiratory systems typified by local pain, tissue edema, hyperemia and functional losses.
In the tissues, immunocompetent cells accumulate at the site of injury
which contribute to tissue damage and perpetuation of the disease
process. Leukotrienes can elicit most, if not all, of these signs and symptoms. Thus, leukotriene
B4 is one of the most powerful chemotactic agents known to date and
participates in the recruitment of leukocytes. The cysteinyl leukotrienes,
on the other hand, contract smooth muscles, particularly in the
peripheral airways and microcirculation of that function leading to the
formation of drugs which block the formation and action of leukotrienes introduced as novel antiasthmatic medications.(2).
3. Leukotrienes in asthma and allergic
rhinitis
Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC(4), LTD(4) and, LTE(4)) and the dihydroxy leukotriene
LTB(4) generated by a series of enzymes/proteins constituting the
LT synthetic pathway or 5-lipoxygenase (5-LO) pathway to
mediate the interaction of multiple receptors. Leukotriene
receptor antagonists (LTRA) and LT synthesis inhibitors (LTSI) have
shown clinical efficacy in asthma and more recently in allergic
rhinitis. Despite growing knowledge of leukotriene biology, the molecular regulation of these inflammatory
mediators remains to be fully understood. Genes encoding enzymes of the
5-LO pathway (i.e. ALOX5, LTC4S and LTA4H) and encoding for LT
receptors (CYSLTR1/2 and LTB4R1/2) provide excellent candidates for
disease susceptibility and severity(3).
4. Treatment heterogeneity in asthma with leukotriene modifiers
Despite advances in treatment, asthma continues to be a significant
health and economic burden. According to the study by the Centers for
Clinical Pediatric Pharmacology & Pharmacogenetics, Jacksonville,
two classes of LT modifiers are 5-lipoxygenase (ALOX5) inhibitors
(zileuton) and leukotriene
receptor antagonists (LTRAs) [montelukast, pranlukast, and
zarfirlukast]. LT modifiers can be used as alternatives to low-dose
inhaled corticosteroids (ICS) in mild persistent asthma, as add-on
therapy to low- to medium-dose ICS in moderate persistent asthma, and as
add-on to high-dose ICS and a long-acting ss2 agonist in severe
persistent asthma. Studies have reported that genetic variation in ALOX5, LTA4H, LTC4S, and ABCC1 influences response to LT modifiers. Plasma concentrations of LTRAs vary considerably among patients(4).
5. Leukotrienes and Fibroblasts
Fibroblasts are implicated in sub-epithelial fibrosis in remodeled
asthmatic airways and contribute to airway inflammation by releasing
cytokines and other mediators. In the study to investigate the expression of leukotriene
biosynthetic enzymes and receptors in primary
fibroblasts from the bronchi of normal and asthmatic adult subjects
using RT-PCR, Western blotting, immunocytochemistry and flow cytometry,
indicated that human bronchial fibroblasts may not only respond to
exogenous leukotrienes but also generate leukotrienes implicated in narrowing, inflammation and remodeling of the asthmatic airway(5).
6. Leukotriene and skin inflammation
Scratching triggers skin flares in atopic dermatitis. According to the study by the Boston Children's Hospital, in mice, tape stripping of mouse skin cause neutrophil influx was largely dependent on the generation of
leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4
receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin
was severely impaired in Ltb4r1(-/-) mice and required expression of
BLT1 on both T cells and non-T cells. Cotransfer of wild-type (WT)
neutrophils, but not neutrophils deficient in BLT1 or the
LTB4-synthesizing enzyme LTA4H, restored the ability of WT CD4(+)
effector T cells to transfer allergic skin inflammation to Ltb4r1(-/-) recipients(6).
7. Leukotriene and local effects
In the study to assess the local effects of intracutaneous injections into humans of 1-3 nmol of five products of arachidonic acid metabolism, leukotrienes
(LT) C4, D4, E4, and B4 from the 5-lipoxygenase pathways and
prostaglandin (PG) D2 from the cyclooxygenase pathway,
clinically and histologically, showed that The dermal vascular sites affected by LTD4 and PGD2 included
capillaries, superficial and deep venules, and arterioles. LTB4 elicited
a transient wheal and flare, followed in 3-4 hr by induration that was
characterized by a dermal infiltrate comprised predominantly of
neutrophils. The combination of LTB4 and PGD2 elicited tenderness and
increased induration associated with a more intense neutrophil
infiltration(7).
8. The functions of The leukotrienes
Leukotrienes
(LTs) are metabolites of arachidonic acid formed by a 5-lipoxygenase and
generated during immunological challenge or by reactions which
involve changes in calcium levels. According to the study by the,
Leukotriene B4 (LTB4), a dihydroxy metabolite, has been shown to exert
marked chemotactic effect in many different animal species. LTB4
probably plays a role in inflammatory responses, and has been detected
in several pathologic conditions. Reaction of LTA4, another lipoxygenase
metabolite of arachidonic acid, with glutathione yields peptidolipid leukotrienes, LTC4, LTD4, and LTE4; these are components of slow reacting substance (SRS and SRS-A). The peptidolipid leukotrienes
are potent bronchoconstrictors and enhance mucus production in the
lungs. Furthermore, they constrict coronary arteries and have a negative
inotropic effect. They probably play an important role in asthma and
anaphylaxis. LTB4 and the peptidolipid leukotrienes may be important in several other organs, too, e.g., the skin and the eye. They may exert effects on a variety of smooth muscles and have neuronal and immunological effects(8).
9. Acetylsalicylic acid (aspirin) in regulation of LTB4 and LTC4
In the sttudy to to investigate the effect of the non-steroidal
anti-inflammatory agent, acetylsalicylic acid (ASA) at different
concentrations on the release rates of the pro-inflammatory mediators,
leukotriene B4 (LTB4) and leukotriene C4 (LTC4), indicated that ASA
treatment at 3 different concentrations (15, 75 and 150 microg/ml), the
release rates of LTB4 and LTC4 were increased from melanocytes of the
normal individuals (13%, 7.5% and 30%; 7.2%, 51.4% and 60.7%,
p<0.001). However, in patients with active vitiligo, the release rate
of LTB4 from melanocytes was decreased (2.9%, 14.4% and 7.4%,
p<0.05), whereas that of LTC4 was increased (3.9%, 93.8% and 101.4%,
p<0.001)(9).
10. Leukotrienes in rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints for which there is no strict cure. According to the study by the Tehran University of Medical Sciences, Leukotrienes
(often leukotriene B4) as potent chemotactic agents can provoke most
signs and symptoms in rheumatoid arthritis by initiating, coordinating,
sustaining, and amplifying the inflammatory response, through
recruitment of leukocytes. A number of studies have reported that
pharmacological modulation in this field can significantly attenuate
clinical manifestations associated with different inflammatory
pathologies(10).
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Sources
(a) http://bmb.oxfordjournals.org/content/43/2/285
(1) http://www.ncbi.nlm.nih.gov/pubmed/23529572
(2) http://www.ncbi.nlm.nih.gov/pubmed/12088275
(3) http://www.ncbi.nlm.nih.gov/pubmed/19416143
(4) http://www.ncbi.nlm.nih.gov/pubmed/17397245
(5) http://www.ncbi.nlm.nih.gov/pubmed/16872537
(6) http://www.ncbi.nlm.nih.gov/pubmed/23063331
(7) http://www.ncbi.nlm.nih.gov/pubmed/6296237
(8) http://www.ncbi.nlm.nih.gov/pubmed/6096644
(9) http://www.ncbi.nlm.nih.gov/pubmed/15494818
(10) http://www.ncbi.nlm.nih.gov/pubmed/23529572
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