Tuesday, 17 December 2013

The Effects of Hormone Leukotrienes(2)

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.
11. Bradykinin, prostaglandins and leukotrienes and Osteoarthritis
Osteoarthritis (OA) of the knee and hip is among the most frequent and debilitating arthritic conditions. According to the study by the McMaster University Faculty of Health Sciences, despite the central involvement of hyaline cartilage in OA pathogenesis, the source of pain likely stems from the richly innervated synovium, subchondral bone and periosteum components of the joint. Tissue damage during joint degeneration generates nociceptive stimuli. The presence of inflammatory mediators, including bradykinin, prostaglandins and leukotrienes, lowers the threshold of the Aδ and C pain fibres, resulting in a heightened response to painful stimuli. it is important to base and centre the management of OA patients on the severity of patient-important outcomes, rather than purely an assessment of damage to the joint. The joint damage, as interpreted from radiographs, is not necessarily representative of the symptoms experienced(11).

12. Leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis
Lipid mediators derived from arachidonic acid through the cyclooxygenase and lipoxygenase pathways are known to be important mediators of inflammation. According to the study by the
James Graham Brown Cancer Center, Louisville, in the study of study of developed mice deficient in BLT2 by targeted disruption, indicated that the BLT2(-/-) mice developed normally, and analysis of immune cells showed that disruption of BLT2 did not alter BLT1 expression or function. Mast cells from the C57BL/6 mice but not from the BLT2(-/-) mice showed intracellular calcium mobilization in response to 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid. In an autoantibody-induced inflammatory arthritis model, the BLT2(-/-) mice showed reduced incidence and severity of disease, including protection from bone and cartilage loss. Reciprocal bone marrow transplant experiments identified that loss of BLT2 expression on a bone marrow-derived cell lineage offers protection against severe disease(12).

13. Excessive synthesis of leukotrienes in the pathogenesis of systemic sclerosis
Systemic sclerosis (SSc, scleroderma) is an autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. SSc-related involvement of the lungs, heart, kidneys and/or the gastrointestinal system accounts for the increased mortality of scleroderma patients. According to the Medical University of Bialystok, Leukotrienes play an important role in the regulation of all the processes vital to the pathogenesis of SSc, namely inflammation, vascular function and connective tissue remodeling. The available data suggests that an excessive synthesis of leukotrienes may contribute to the development and progression of SSc. Accordingly, blockade of leukotriene pathways appears to be a new, promising target for the treatment of SSc(13).

14. Inhibition of leukotriene D4 and eosinophilic gastroenteritis
Eosinophilic Gastroenteritis (EG) is a rare condition, caused by eosinophilic inflammatory infiltrates in the gastrointestinal tract. It is usually treated successfully with systemic glucocorticoids. According to the study by the Department of internal medicine, UZ Leuven,  montelukast, a leukotriene receptor antagonist inhibits leukotriene D4, an important cytokine in the inflammatory cascade. Although montelukast could not replace steroid therapy, it acted as a steroid sparing agent in our patient(14).

15. Churg-Strauss and the Inhibition of leukotriene D4
Churg-Strauss syndrome (CSS) is a systemic small vessel vasculitis involving lungs, skin, heart, gastrointestinal tract and peripheral nerves. According to the study lead by Carlesimo M, there is a report of a 36-year-old woman with a necrotic lesion on the left foot of two months duration, associated with hypereosinophilia, patchy lung infiltrates, cardiac damage and a mononeuritis. The personal history was remarkable only for an asthma, treated with Montelukast, a leukotriene receptor antagonist (LRA). Clinical symptoms, laboratory exams and instrumental examinations led us to the diagnosis of CSS. In recent years several studies have reported the possible relationship between use of leukotriene receptor antagonist (LRA) and CSS expression(15).

16. Treatment of asthma with antileukotrienes and Churg-Strauss syndrome
Since antileukotriene treatment for asthma was introduced, there has been debate about whether such therapy can lead to Churg-Strauss Syndrome (CSS). According to Hospital Central de Asturias, Oviedo, Hospital Puerta de Hierro, there is a report of which suspected CSS in a patient with bronchopulmonary, cutaneous and analytical signs and whom we treated with oral steroids. After clinical improvement, one year later, steroids were replaced by antileukotrienes, after which the same clinical picture developed. The vasculitis characteristic of CSS was confirmed pathologically(16).

17. Leukotrienes: the immune-modulating lipid mediators of disease
The leukotrienes are important lipid mediators with immune modulatory and proinflammatory properties. When formed in excess, these compounds play a pathogenic role in several acute and chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease. According to the study by the Department of Medical Biochemistry and Biophysics, Division of Chemistry 2, Karolinska Institutet, Classical bioactions of leukotrienes include chemotaxis, endothelial adherence, and activation of leukocytes, chemokine production, as well as contraction of smooth muscles in the microcirculation and respiratory tract. Recent genetic, morphological, and biochemical approaches, have pointed to the involvement of leukotrienes in cardiovascular diseases including atherosclerosis, myocardial infarction, stroke, and abdominal aortic aneurysm. Moreover, new insights have changed our previous notion of leukotrienes as mediators of inflammatory reactions to molecules that can fine-tune the innate and adaptive immune response(17).

18. Trihydroxyflavones and the inflammatory processes
In the study to evaluate the anti-inflammatory potential of a series of trihydroxyflavones by testing their ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) in cells and cell-free systems and to inhibit the proinflammatory pathways mediated by the enzymes cyclooxygenase (COX) and 5-lipoxygenase (5-LOX), in which reactive species have a proven involvement, showed that The tested trihydroxyflavones proved to be effective inhibitors of neutrophils' oxidative burst and were shown to scavenge different ROS and RNS in cell-free systems. The most active compound in the majority of the assays was 3,3',4'-trihydroxyflavone, which was somehow expected due to the presence of the ortho-dihydroxy in the B-ring, an important structural feature in terms of free radical scavenging activity and the compounds were able to inhibit the production of leukotriene B(4) by 5-LOX in activated neutrophils. 3,5,7-Trihydroxyflavone was able to inhibit both COX-1 and COX-2, which makes it a dual inhibitor of COX and 5-LOX pathways and, therefore, a promising candidate for a new therapeutic option in the treatment of inflammatory processes(18).

19. Leukotrienes and neuropathic/inflammatory pain
In the study to summarize the recent studies examining the expression of leukotrienes (LTs) and their receptors in nociceptive pathways, and their crucial roles in pathological pain conditions, by examininf of  whether LTs were implicated in neuropathic pain following peripheral nerve injury. Using the SNI model in rats, investigating the expression of LT synthases and receptors mRNAs in the spinal cord and the roles on the pain behaviors, showed that the increase of LT synthesis in spinal microglia produced via p38 mitogen-activated protein kinase (MAPK) plays a role in the generation of neuropathic pain. We also examined the expression and roles on pain behaviors of LT receptors in the dorsal root ganglion (DRG) using a peripheral inflammation model. The data indicate CysLT2 expressed in DRG neurons may play a role as a modulator of P2X3, and contribute to the potentiation of the neuronal activity following peripheral inflammation(19).

20. Lukotrienes in the pathogenesis of dysmenorrhea in adolescent girls
In the study to determine the role of prostaglandins and leukotrienes in the pathogenesis of dysmenorrhea in a data of  Twenty patients with dysmenorrhea aged 16.2+/-1.2 years and 20 healthy age-matched controls with eumenorrhea (absence of pain during menstruation) showed that there is a distinct pattern of leukotriene production during the menstrual cycle, but the changes in the systemic level are not responsible for their role in the pathogenesis of dysmenorrhea. Further studies at the local level in the target organ are necessary to elucidate the role of the lipid mediators in the pathogenesis of dysmenorrhea(20).
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(11) http://www.ncbi.nlm.nih.gov/pubmed/22471357
(12) http://www.ncbi.nlm.nih.gov/pubmed/20656922
(13) http://www.ncbi.nlm.nih.gov/pubmed/22763975
(14) http://www.ncbi.nlm.nih.gov/pubmed/22319970
(15) http://www.ncbi.nlm.nih.gov/pubmed/22230414
(16) http://www.ncbi.nlm.nih.gov/pubmed/11181230
(17) http://www.ncbi.nlm.nih.gov/pubmed/23063073
(18) http://www.ncbi.nlm.nih.gov/pubmed/22806885
(19) http://www.ncbi.nlm.nih.gov/pubmed/21804200
(20) http://www.ncbi.nlm.nih.gov/pubmed/19227413  

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