Monday, 16 December 2013

The Effects of Hormone Leukotrienes(1)

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).
Chinese Secrets To Fatty Liver And Obesity Reversal
Use The Revolutionary Findings To Achieve 
Optimal Health And Loose Weight

Super foods Library, Eat Yourself Healthy With The Best of the Best Nature Has to Offer

Back to Hormones

Back to Kyle J. Norton Home page   


No comments:

Post a comment