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1
Uotila, P., K. Punnonen, R. Tammivaara und CT Jansén. „Detection of leukotrienes in the serum of asthmatic and psoriatic patients“. Acta Dermato-Venereologica 66, Nr. 5 (01.09.1986): 381–85. http://dx.doi.org/10.2340/0001555566381385.
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Purified serum samples from asthmatic and psoriatic patients and healthy controls were analysed by high-pressure liquid chromatography (HPLC) and the amounts of leukotrienes were measured from the corresponding HPLC fractions by specific radioimmunoassays. In the serum of healthy controls the amounts of leukotrienes B4, C4 and D4 were very small or negligible. Rather great amount of leukotriene B4 was, however, detected in the serum of many asthmatic and psoriatic patients. The amount of leukotriene B4 was in the serum of asthmatic patients 120 +/- 20 pmol/ml (n = 11, mean +/- SEM) and in that of psoriatic patients 100 +/- 10 pmol/ml (n = 10). The amounts of leukotrienes C4 and D4 were rather small in the serum of most patients. The amount of leukotriene C4 was, however, very high (250 pmol/ml) in the serum of a psoriatic patient. Significant amount of leukotriene D4 was also detected in the serum of this patient. The present study indicated that leukotrienes are formed during blood clotting in the leukocytes of asthmatic and psoriatic patients and that the rate of formation is so high that leukotrienes may have a role in these diseases.
2
Paterson, N. A. „Influence of hypoxia on histamine and leukotriene release from dispersed porcine lung cells“. Journal of Applied Physiology 61, Nr. 5 (01.11.1986): 1790–95. http://dx.doi.org/10.1152/jappl.1986.61.5.1790.
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The ability of hypoxia (PO2 57 Torr) and anoxia (PO2 0 Torr) to induce the release of histamine or sulfidopeptide leukotrienes from dispersed porcine parenchymal lung cells was examined. Spontaneous release of histamine (9.2 +/- 1.3%) was not significantly increased during hypoxia or anoxia, and spontaneous leukotriene release was not detected under any conditions. The release of leukotriene induced by A23187 (78 +/- 11 pmol leukotriene D4 equivalent/10(7) parenchymal lung cells) was unchanged during hypoxia and was significantly reduced (55.4 +/- 7.7% control leukotriene release) during anoxia, whereas A23187-induced histamine release (63.2 +/- 4.2% total cell histamine) was unaffected by reduced oxygenation. Reduction of final buffer pH from 7.4 to 7.0 did not affect mediator release. High-pressure liquid chromatographic analysis of the released leukotrienes revealed a mixture of leukotrienes C4 and D4, with a symmetrical reduction in product during anoxia. Although leukotriene release in response to hypoxia was not demonstrated, the findings do not preclude limited local release of leukotrienes, perhaps in association with increased smooth muscle responsiveness.
3
Petersen, Bodil, K. Frank Austen, Kenneth D. Bloch, Yukako Hotta, Fumito Ichinose, Yoshihide Kanaoka und Warren M. Zapol. „Cysteinyl Leukotrienes Impair Hypoxic Pulmonary Vasoconstriction in Endotoxemic Mice“. Anesthesiology 115, Nr. 4 (01.10.2011): 804–11. http://dx.doi.org/10.1097/aln.0b013e31822e94bd.
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Background Sepsis impairs hypoxic pulmonary vasoconstriction (HPV) in patients and animal models, contributing to systemic hypoxemia. Concentrations of cysteinyl leukotrienes are increased in the bronchoalveolar lavage fluid of patients with sepsis, but the contribution of cysteinyl leukotrienes to the impairment of HPV is unknown. Methods Wild-type mice, mice deficient in leukotriene C(4) synthase, the enzyme responsible for cysteinyl leukotriene synthesis, and mice deficient in cysteinyl leukotriene receptor 1 were studied 18 h after challenge with either saline or endotoxin. HPV was measured by the increase in left pulmonary vascular resistance induced by left mainstem bronchus occlusion. Concentrations of cysteinyl leukotrienes were determined in the bronchoalveolar lavage fluid. Results In the bronchoalveolar lavage fluid of all three strains, cysteinyl leukotrienes were not detectable after saline challenge; whereas endotoxin challenge increased cysteinyl leukotriene concentrations in wild-type mice and mice deficient in cysteinyl leukotriene receptor 1, but not in mice deficient in leukotriene C(4) synthase. HPV did not differ among the three mouse strains after saline challenge (120 ± 26, 114 ± 16, and 115 ± 24%, respectively; mean ± SD). Endotoxin challenge markedly impaired HPV in wild-type mice (41 ± 20%) but only marginally in mice deficient in leukotriene C(4) synthase (96 ± 16%, P < 0.05 vs. wild-type mice), thereby preserving systemic oxygenation. Although endotoxin modestly decreased HPV in mice deficient in cysteinyl leukotriene receptor 1 (80 ± 29%, P < 0.05 vs. saline challenge), the magnitude of impairment was markedly less than in endotoxin-challenged wild-type mice. Conclusion Cysteinyl leukotrienes importantly contribute to endotoxin-induced impairment of HPV in part via a cysteinyl leukotriene receptor 1-dependent mechanism.
4
Jackson, W. F. „Regional differences in mechanism of action of oxygen on hamster arterioles“. American Journal of Physiology-Heart and Circulatory Physiology 265, Nr. 2 (01.08.1993): H599—H603. http://dx.doi.org/10.1152/ajpheart.1993.265.2.h599.
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Leukotrienes have been implicated in the arteriolar constriction induced by elevated PO2 in the hamster cheek pouch. The role of leukotrienes in arteriolar O2 reactivity in other tissues has not been studied. To test the hypothesis that leukotrienes mediate O2 reactivity in all tissues, the effects of a leukotriene receptor antagonist, SKF-102922 (10 microM), a 5-lipoxygenase inhibitor, SC-43251 (30 microM), and a 5-lipoxygenase-activating protein antagonist, MK-886 (10 microM), on arteriolar O2 reactivity in hamster cheek pouch were compared with their effects on cremasteric arteriolar O2 reactivity. All three agents significantly decreased O2-induced arteriolar constriction in the cheek pouch, as reported previously. However, none of the antagonists inhibited O2-induced constriction of cremasteric arterioles. The efficacy of the leukotriene receptor antagonist, SKF-102922, was verified in the cremaster muscle: 10 microM SKF-102922 completely abolished constriction induced by topical application of leukotriene D4. These data support the hypothesis that leukotrienes mediate O2 reactivity in the cheek pouch. However, leukotrienes do not appear to mediate O2 reactivity in the cremaster muscle. These data suggest that there are significant regional differences in the mechanism of action of O2 on arterioles.
5
Denzlinger, C., A. Kapp, M. Grimberg, HH Gerhartz und W. Wilmanns. „Enhanced endogenous leukotriene biosynthesis in patients treated with granulocyte-macrophage colony-stimulating factor“. Blood 76, Nr. 9 (01.11.1990): 1765–70. http://dx.doi.org/10.1182/blood.v76.9.1765.1765.
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Abstract The hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is being used in clinical trials for its potential in the treatment of hematopoietic insufficiency due to various causes. Involvement of leukotrienes in the effects of GM-CSF is suggested by analytical and pharmacologic evidence obtained in vitro. However, until now no data in support of a role of leukotrienes in GM-CSF action in vivo have been presented. In the present investigation this question was approached by measurement of endogenous cysteinyl leukotriene formation in patients treated with the cytokine for cytopenia induced by cytostatic drugs or for refractory anemia with excess of blasts (RAEB). Endogenous cysteinyl leukotriene formation was assessed by determination of urinary leukotriene metabolites using combined high- performance liquid chromatography and radioimmunoassay analysis. After GM-CSF administration a distinct increase in urinary cysteinyl leukotrienes was found in the cytopenic and the RAEB patients that ranged from 2.3- to 57-fold and 2.4- to 333-fold, respectively. In the cytopenic patients the increase in leukotriene production was correlated to an expansion of peripheral blood leukocytes; RAEB patients responded to GM-CSF with enhanced leukotriene biosynthesis even if the peripheral leukocytes decreased, possibly due to an abnormal number and/or irritability of leukotriene-producing cells. The increase in endogenous leukotriene production during therapy with GM- CSF may indicate that leukotrienes play a role in GM-CSF action in vivo.
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Denzlinger, C., A. Kapp, M. Grimberg, HH Gerhartz und W. Wilmanns. „Enhanced endogenous leukotriene biosynthesis in patients treated with granulocyte-macrophage colony-stimulating factor“. Blood 76, Nr. 9 (01.11.1990): 1765–70. http://dx.doi.org/10.1182/blood.v76.9.1765.bloodjournal7691765.
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The hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is being used in clinical trials for its potential in the treatment of hematopoietic insufficiency due to various causes. Involvement of leukotrienes in the effects of GM-CSF is suggested by analytical and pharmacologic evidence obtained in vitro. However, until now no data in support of a role of leukotrienes in GM-CSF action in vivo have been presented. In the present investigation this question was approached by measurement of endogenous cysteinyl leukotriene formation in patients treated with the cytokine for cytopenia induced by cytostatic drugs or for refractory anemia with excess of blasts (RAEB). Endogenous cysteinyl leukotriene formation was assessed by determination of urinary leukotriene metabolites using combined high- performance liquid chromatography and radioimmunoassay analysis. After GM-CSF administration a distinct increase in urinary cysteinyl leukotrienes was found in the cytopenic and the RAEB patients that ranged from 2.3- to 57-fold and 2.4- to 333-fold, respectively. In the cytopenic patients the increase in leukotriene production was correlated to an expansion of peripheral blood leukocytes; RAEB patients responded to GM-CSF with enhanced leukotriene biosynthesis even if the peripheral leukocytes decreased, possibly due to an abnormal number and/or irritability of leukotriene-producing cells. The increase in endogenous leukotriene production during therapy with GM- CSF may indicate that leukotrienes play a role in GM-CSF action in vivo.
7
Jones, T. R., Y. Guindon, R. Young, E. Champion, L. Charette, D. Denis, D. Ethier et al. „L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylsulfonyl]-γ-oxo-benzenebutanoate: a leukotriene D4 receptor antagonist“. Canadian Journal of Physiology and Pharmacology 64, Nr. 12 (01.12.1986): 1535–42. http://dx.doi.org/10.1139/y86-258.
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L-648,051, sodium 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]-γ-oxo-benzenebutanoate is a selective and competitive inhibitor of [3H]leukotriene D4 (KB value of 4.0 μM) and to a lesser extent [3H]leukotriene C4 (Ki value of 36.7 μM) binding in guinea pig lung homogenates. Functionally, it selectively antagonized contractions of guinea pig trachea induced by leukotrienes C4, D4, E4, and F4 in concentrations that did not antagonize contractions induced by acetylcholine, histamine, serotonin, prostaglandin F2α, or U-44069 (endoperoxide analogue). Schild plot analysis indicated that L-648,051 competitively antagonized contractions of guinea pig ileum induced by leukotriene D4 (pA2 7.7) and contractions of trachea induced by leukotrienes D4, E4, and F4 (pA2 7.3, 7.4, and 7.5, respectively). Contractions of guinea pig trachea induced by leukotriene C4 were inhibited in a noncompetitive fashion (Schild plot slope, 0.45). Developed contractions of trachea induced by the leukotrienes were rapidly reversed by L-648,051 > FPL-55712 > L-649,923. Intravenous L-648,051 selectively blocked bronchoconstriction induced in anaesthetized guinea pigs by intravenous leukotrienes C4, D4, and E4 but not that induced by arachidonic acid, serotonin, U-44069, or acetylcholine. The compound displayed poor activity following intraduodenal administration. The profile of activity for L-648,051 indicates that it may be a useful topical agent for studying the role of leukotrienes in diseases such as bronchial asthma.
8
Mancuso, Peter, Theodore J. Standiford, Teresa Marshall und Marc Peters-Golden. „5-Lipoxygenase Reaction Products Modulate Alveolar Macrophage Phagocytosis of Klebsiella pneumoniae“. Infection and Immunity 66, Nr. 11 (01.11.1998): 5140–46. http://dx.doi.org/10.1128/iai.66.11.5140-5146.1998.
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ABSTRACT The leukotrienes are potent lipid mediators of inflammation formed by the 5-lipoxygenase-catalyzed oxidation of arachidonic acid. Although the effects of leukotrienes on neutrophil chemotaxis and activation have been established, their role in modulating innate host defense mechanisms is poorly understood. In a previous study (M. Bailie, T. Standiford, L. Laichalk, M. Coffey, R. Strieter, and M. Peters-Golden, J. Immunol. 157:5221–5224, 1996), we used 5-lipoxygenase knockout mice to establish a critical role for endogenous leukotrienes in pulmonary clearance and alveolar macrophage phagocytosis ofKlebsiella pneumoniae. In the present study, we investigated the role of specific endogenous leukotrienes in phagocytosis of K. pneumoniae and explored the possibility that exogenous leukotrienes could restore phagocytosis in alveolar macrophages with endogenous leukotriene synthesis inhibition and enhance this process in leukotriene-competent cells. Rat alveolar macrophages produced leukotriene B4 (LTB4), LTC4, and 5-hydoxyeicosatetraenoic acid (5-HETE) during the process of phagocytosis, and the inhibition of endogenous leukotriene synthesis with zileuton and MK-886 dramatically attenuated phagocytosis. We also observed a reduction in phagocytosis when we treated alveolar macrophages with antagonists to the plasma membrane receptors for either LTB4, cysteinyl-leukotrienes, or both. In leukotriene-competent cells, LTC4 augmented phagocytosis to the greatest extent, followed by 5-HETE and LTB4. These 5-lipoxygenase reaction products demonstrated similar relative abilities to reconstitute phagocytosis in zileuton-treated rat alveolar macrophages and in alveolar macrophages from 5-lipoxygenase knockout mice. We conclude that endogenous synthesis of all major 5-lipoxygenase reaction products plays an essential role in phagocytosis. The restorative and pharmacologic effects of LTC4, LTB4, and 5-HETE may provide a basis for their exogenous administration as an adjunctive treatment for patients with gram-negative bacterial pneumonia.
9
Meshram, Deepak, Khushbo Bhardwaj, Charulata Rathod, Gail B. Mahady und Kapil K. Soni. „The Role of Leukotrienes Inhibitors in the Management of Chronic Inflammatory Diseases“. Recent Patents on Inflammation & Allergy Drug Discovery 14, Nr. 1 (30.03.2020): 15–31. http://dx.doi.org/10.2174/1872213x14666200130095040.
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Background: Leukotrienes are powerful mediators of inflammation and interact with specific receptors in target cell membrane to initiate an inflammatory response. Thus, Leukotrienes (LTs) are considered to be potent mediators of inflammatory diseases including allergic rhinitis, inflammatory bowel disease and asthma. Leukotriene B4 and the series of cysteinyl leukotrienes (C4, D4, and E4) are metabolites of arachidonic acid metabolism that cause inflammation. The cysteinyl LTs are known to increase vascular permeability, bronco-constriction and mucus secretion. Objectives: To review the published data for leukotriene inhibitors of plant origin and the recent patents for leukotriene inhibitors, as well as their role in the management of inflammatory diseases. Methods: Published data for leukotrienes antagonists of plant origin were searched from 1938 to 2019, without language restrictions using relevant keywords in both free text and Medical Subject Headings (MeSH terms) format. Literature and patent searches in the field of leukotriene inhibitors were carried out by using numerous scientific databases including Science Direct, PubMed, MEDLINE, Google Patents, US Patents, US Patent Applications, Abstract of Japan, German Patents, European Patents, WIPO and NAPRALERT. Finally, data from these information resources were analyzed and reported in the present study. Results: Currently, numerous anti-histaminic medicines are available including chloropheneremine, brompheniramine, cetirizine, and clementine. Furthermore, specific leukotriene antagonists from allopathic medicines are also available including zileuton, montelukast, pranlukast and zafirlukast and are considered effective and safe medicines as compared to the first generation medicines. The present study reports leukotrienes antagonistic agents of natural products and certain recent patents that could be an alternative medicine in the management of inflammation in respiratory diseases. Conclusion: The present study highlights recent updates on the pharmacology and patents on leukotriene antagonists in the management of inflammation respiratory diseases.
10
Steinhilber, D. „5-Lipoxygenase: A Target for Antiinflammatory Drugs Revisited“. Current Medicinal Chemistry 6, Nr. 1 (Januar 1999): 71–85. http://dx.doi.org/10.2174/0929867306666220207211259.
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Abstract: Arachidonate 5-lipoxygenase is the key enzyme in leukotriene biosynthesis and catalyzes the initial steps in the conversion of arachidonic acid to biologically active leukotrienes. Leukotrienes are considered as potent potent mediators of inflammatory and allergic reactions which are locally released by leukocytes and other 5-LO expressing cells and exert their effects via binding to specific membrane receptors and, as suggested recently, the nuclear receptor PPARa. Because of the proinflammatory profile of leukotrienes it was assumed that leukotriene biosynthesis inhibitors and leukotriene receptor antagonists have a therapeutical potential in a variety of inflammatory diseases. Clinical studies confirmed the therapeutic value of the antileukotriene therapy in asthma but the results with leukotriene biosynthesis inhibitors in psoriasis, arthritis and inflammatory bowel disease were more or less disappointing. This review summarizes the biochemistry of the 5-lipoxygenase pathway, the pharmacology of FLAP and 5-lipoxygenase inhibitors and discusses possible criteria for the development of these drugs.
11
Craft, D. V., D. J. Lefer, C. E. Hock und A. M. Lefer. „Significance of production of peptide leukotrienes in murine traumatic shock“. American Journal of Physiology-Heart and Circulatory Physiology 251, Nr. 1 (01.07.1986): H80—H85. http://dx.doi.org/10.1152/ajpheart.1986.251.1.h80.
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We studied the formation of a leukotriene metabolite in plasma and bile during traumatic shock. Anesthetized rats subjected to Noble-Collip drum trauma developed a lethal shock state characterized by a survival time of 1.9 +/- 0.3 h, a 4.5-fold increase in plasma cathepsin D activity, and a reduction in mean arterial blood pressure to 45 +/- 2 mmHg compared with 108 +/- 5 mmHg in sham-shock controls. Plasma and bile samples were analyzed by reverse-phase high-pressure liquid chromatography (HPLC) for peptide leukotrienes (e.g., LTC4, LTD4, and LTE4), and their retention times were confirmed by co-elution with radioactive standards, radioimmunoassay (RIA), and UV spectrophotometry. No leukotrienes or metabolites were found in plasma. The major peptide leukotriene from bile was eluted between LTC4 and LTD4 and corresponds to a metabolite of LTE4, N-acetyl-LTE4, which is also produced during endotoxin shock. The metabolite increased nearly sevenfold in traumatic shock compared with sham trauma. The identity of the metabolite was confirmed by UV scan, which revealed a spectrum consistent with a peptide leukotriene and similar to that of previously reported spectra for N-acetyl-LTE4. In conclusion, peptide leukotrienes are rapidly cleared from the blood and appear in the bile as N-acetyl-LTE4, a metabolite of the peptide leukotrienes. These findings support a role of the peptide leukotrienes in the pathogenesis of traumatic shock.
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Hagmann, W. „Cell proliferation status, cytokine action and protein tyrosine phosphorylation modulate leukotriene biosynthesis in a basophil leukaemia and a mastocytoma cell line“. Biochemical Journal 299, Nr. 2 (15.04.1994): 467–72. http://dx.doi.org/10.1042/bj2990467.
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Mast cells, mastocytoma cells and basophil leukaemia cells are well-established producers of leukotrienes when grown and stimulated appropriately. I report that the cells' ability to produce leukotrienes is dependent on the cells' proliferative status or their provision with growth factors. Proliferating MC/9 and subconfluent RBL2H3 cells respond maximally to stimulation by 1 microM ionomycin with the production of 56 and 32 pmol of cysteinyl-leukotrienes/10(6) cells respectively. In contrast, confluent RBL2H3 or growth-arrested MC/9 cells lose their ability to generate leukotrienes in response to ionomycin treatment. This rapid down-regulation of leukotriene synthesis is also observed when proliferating RBL2H3 cells are transferred to growth-factor-free medium, wherein cellular leukotriene-synthesis capacity has an apparent half-lifetime of 60 min. Transfer back into growth medium results in the regeneration of leukotriene synthesis capacity within 6 h. In growth-arrested MC/9 cells, leukotriene production ability can at least partially be restored by priming the cells with interleukin 3, but not with interleukin 4. In RBL2H3 cells, pretreatment with protein tyrosine kinase inhibitors such as genistein (5 min, 37 microM), herbimycin A (6 h, 3 microM) or tyrphostin 25 (16 h, 100 microM) completely inhibits leukotriene generation, whereas okadaic acid (15 min, 0.5 microM) has no effect. Under these conditions, both genistein and herbimycin A strongly impair ionomycin-induced protein tyrosine phosphorylation. Our study indicates that leukotriene generation in these tumour cells is tightly regulated by their proliferation status and supply with growth factors, and cell stimulation towards leukotriene synthesis appears to involve protein tyrosine kinase activity.
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Jaeschke, H., M. J. Raftery, U. Justesen und S. J. Gaskell. „Serum complement mediates endotoxin-induced cysteinyl leukotriene formation in rats in vivo“. American Journal of Physiology-Gastrointestinal and Liver Physiology 263, Nr. 6 (01.12.1992): G947—G952. http://dx.doi.org/10.1152/ajpgi.1992.263.6.g947.
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To investigate potential mediators responsible for cysteinyl leukotriene formation during endotoxemia, male Fischer rats received an intravenous bolus injection of 5 mg/kg Salmonella enteritidis endotoxin and cysteinyl leukotrienes were measured by gas chromatography-mass spectrometry. The biliary excretion of leukotriene (LT) C4 (0.20 +/- 0.02 pmol.min-1.g liver-1) and N-acetyl-LTE4 (0.37 +/- 0.07 pmol.min-1.g-1) was increased by 190 and 1,000%, respectively, during the first 30 min after endotoxin injection. Endotoxin also caused a temporary reduction of hepatic ATP levels by 84%. Depletion of serum complement almost completely abolished the endotoxin-induced increase of cysteinyl leukotrienes in bile without affecting the biliary excretion mechanism. Intravenous injection of activated complement factors caused cysteinyl leukotriene formation and reduced the hepatic ATP content similar to endotoxin. Depletion of glutathione in the liver prevented cysteinyl leukotriene formation and the complement-induced ATP depletion. It is concluded that endotoxin-induced cysteinyl leukotriene generation in vivo is mediated predominantly through activation of complement. The vasoconstrictive cysteinyl leukotrienes are then responsible for ATP depletion in the liver.
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Ochkur, Sergei, Cheryl Protheroe, Wen Li, Dana Colbert, Katie Zellner, James Lee und Nancy Lee. „Cys-leukotrienes mediate lung dysfunction but not histopathologies in an IL-5/Eotaxin-2 double transgenic mouse model of severe asthma (163.13)“. Journal of Immunology 186, Nr. 1_Supplement (01.04.2011): 163.13. http://dx.doi.org/10.4049/jimmunol.186.supp.163.13.
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Abstract Products of the 5-lipoxygenase (5-LO) pathway (i.e., cys-leukotrienes and LTB4), are contributors to lung inflammation, airway remodeling, and hyperresponsiveness associated with allergic respiratory inflammation. Eosinophils are capable of leukotriene synthesis/secretion and chemotactically respond to these compounds. However, the in vivo role of eosinophils in leukotriene mediated events during asthmatic airway inflammation is not defined. To study the link between eosinophils and leukotrienes we used the I5/E2 double transgenic mouse model of severe asthma, over-expressing IL-5 systemically and eotaxin-2 in airways, in which lung pathologies are entirely dependent on the presence of eosinophils. We show that airway levels of cysteinyl leukotrienes and LTB4 are significantly elevated in I5/E2 mice. Crosses of I5E2 mice with 5-LO knockout animals abolished AHR in the I5/E2 parental model without significant effects on lung histopathology. Administration of a cys-leukotriene receptor antagonist (Montelukast®) to I5/E2 mice replicates the effects of the total leukotriene loss in I5/E2/5-LO-/- animals. In contrast, I5/E2 mice crossed with BLT-1-/- mice which are deficient of the LTB4 receptor fail to display effects on the pulmonary pathologies occurring in the I5/E2 parental model. These data demonstrate a unique role for cys-leukotrienes in the development of AHR independent of lung remodeling events occurring in this transgenic model of severe asthma.
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Unterberg, Andreas, Walter Schmidt, Michael Wahl, Earl F. Ellis, Anthony Marmarou und Alexander Baethmann. „Evidence against leukotrienes as mediators of brain edema“. Journal of Neurosurgery 74, Nr. 5 (Mai 1991): 773–80. http://dx.doi.org/10.3171/jns.1991.74.5.0773.
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✓ Leukotrienes are powerful metabolites of arachidonic acid which are known to increase the permeability of peripheral blood vessels. These substances are found in brain tissue in association with cerebral ischemia, and in brain tumors. Therefore, it has been proposed that leukotrienes have a mediator function in brain edema. This hypothesis was subjected to further experimental analysis in this study, in which the authors investigated whether: 1) superfusion of the exposed brain surface with leukotrienes increases the permeability of extraparenchymal blood vessels in vivo; 2) intraparenchymal infusion of leukotrienes induces brain edema; and 3) pharmacological inhibition of leukotriene formation by BW755C, an inhibitor of leukotriene synthesis, reduces formation of brain edema from a standardized traumatic insult. The pial vessels of the parietal cortex of cats were examined by fluorescence microscopy during cerebral superfusion with the leukotrienes C4 (LTC4), D4 (LTD4), or E4 (LTE4) by using an open cranial window preparation. Intravenous Na+-fluorescein served as an in vivo blood-brain barrier (BBB) indicator. Superfusion of the pia with leukotrienes (up to 2 µM) did not open the barrier to fluorescein, but was associated with a significant constriction (up to 25%) of arterial and venous vessels. In experiments with slow infusion of leukotriene B4 (LTB4) or LTC4 into the white matter of feline brain, the tissue water content was subsequently determined in serial brain slices using the specific gravity method. Tissue water profiles obtained after a 15- µM infusion of either LTB4 or LTC4 were virtually identical with those of control animals infused with mock cerebrospinal fluid. Thus, neither LTB4 nor LTC4 led to an augmentation of infusion-induced brain edema. In a final series, a cold lesion of the left parietal cortex was induced in rabbits. Twenty-four hours later, swelling of the exposed hemisphere was quantified by gravimetrical comparison of its weight with that of the contralateral nontraumatized hemisphere. Eight animals received BW755C intravenously prior to and after trauma to inhibit formation of leukotrienes. Seven rabbits were infused with an equivalent volume of saline as a control study. The resulting hemispheric swelling was 7.7% ± 0.6% (mean ± standard error of the mean) 24 hours later in animals receiving BW755C and 7.8% ± 1.2% in the control group, indicating that inhibition of leukotrienes was ineffective in preventing formation of vasogenic brain edema. The findings demonstrate that leukotrienes administered to the brain in concentrations occurring under pathological conditions do not open the BBB nor do they induce brain edema. Moreover, formation of brain edema from a standard insult was not therapeutically influenced by inhibition of leukotriene synthesis. Thus, the current findings taken together do not support a role of leukotrienes as mediators in brain edema.
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Larsen, Julie S., und Edward P. Acosta. „Leukotriene-Receptor Antagonists and 5-Lipoxygenase Inhibitors in Asthma“. Annals of Pharmacotherapy 27, Nr. 7-8 (Juli 1993): 898–903. http://dx.doi.org/10.1177/106002809302700718.
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OBJECTIVE: To familiarize readers with a potentially new class of compounds for treating asthma. Background information on leukotrienes is provided in addition to an indepth review of pertinent clinical trials. DATA SOURCES: Information was obtained from controlled clinical trials, abstracts, and review articles identified through a MEDLINE search of English-language articles. STUDY SELECTION: Emphasis was placed on early clinical trials that showed some benefit with these compounds as well as more recent studies using newer agents that produced more promising results. DATA EXTRACTION: Information regarding leukotriene biochemistry was extracted from basic science research and data from human studies were evaluated by the authors according to patient selection, study design, methodology, and therapeutic response. DATA SYNTHESIS: Leukotrienes have a pathophysiologic role in asthma. Two distinct but pharmacologically similar classes of leukotriene inhibitors are currently being clinically evaluated. These are leukotriene receptor antagonists and 5-lipoxygenase inhibitors. Early clinical trials with these agents yielded unfavorable results primarily because of lack of drug potency and selectivity, poor patient tolerance, and possibly the route of administration. Subsequent studies with more potent and selective agents have further implicated leukotrienes as biochemical mediators in asthma and, consequently, have shown promising clinical outcomes with respect to pulmonary function testing and patient tolerance. CONCLUSIONS: Advancements in the pathogenesis of asthma are beginning to define a role for the leukotrienes. Although more studies are needed to assess the efficacy of leukotriene inhibitors, recent clinical trials using leukotriene-receptor antagonists and 5-lipoxygenase inhibitors indicate a potential for the expansion of therapeutic regimens currently used in the treatment of asthma.
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Murphy, Robert C., und Miguel A. Gijón. „Biosynthesis and metabolism of leukotrienes“. Biochemical Journal 405, Nr. 3 (13.07.2007): 379–95. http://dx.doi.org/10.1042/bj20070289.
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Leukotrienes are metabolites of arachidonic acid derived from the action of 5-LO (5-lipoxygenase). The immediate product of 5-LO is LTA4 (leukotriene A4), which is enzymatically converted into either LTB4 (leukotriene B4) by LTA4 hydrolase or LTC4 (leukotriene C4) by LTC4 synthase. The regulation of leukotriene production occurs at various levels, including expression of 5-LO, translocation of 5-LO to the perinuclear region and phosphorylation to either enhance or inhibit the activity of 5-LO. Several other proteins, including cPLA2α (cytosolic phospholipase A2α) and FLAP (5-LO-activating protein) also assemble at the perinuclear region before production of LTA4. LTC4 synthase is an integral membrane protein that is present at the nuclear envelope; however, LTA4 hydrolase remains cytosolic. Biologically active LTB4 is metabolized by ω-oxidation carried out by specific cytochrome P450s (CYP4F) followed by β-oxidation from the ω-carboxy position and after CoA ester formation. Other specific pathways of leukotriene metabolism include the 12-hydroxydehydrogenase/15-oxo-prostaglandin-13-reductase that forms a series of conjugated diene metabolites that have been observed to be excreted into human urine. Metabolism of LTC4 occurs by sequential peptide cleavage reactions involving a γ-glutamyl transpeptidase that forms LTD4 (leukotriene D4) and a membrane-bound dipeptidase that converts LTD4 into LTE4 (leukotriene E4) before ω-oxidation. These metabolic transformations of the primary leukotrienes are critical for termination of their biological activity, and defects in expression of participating enzymes may be involved in specific genetic disease.
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Heller, R. Scott, R. Peter Herman und Ceil A. Herman. „The action and metabolism of peptide leukotrienes in the isolated bullfrog lung“. Canadian Journal of Physiology and Pharmacology 67, Nr. 4 (01.04.1989): 309–14. http://dx.doi.org/10.1139/y89-050.
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Leukotrienes (LTs) have been shown to cause contraction of mammalian airway smooth muscle. In this study, LTC4, LTD4, and LTE4 were tested on isolated strips of bullfrog lung. LTC4, LTD4, and LTE4 (10−7 to 3 × 10−10 M) stimulated lung contraction. LTC4 was the most potent, with LTD4 and LTE4 being of equal but lower potency. The cyclooxygenase inhibitors, indomethacin and ibuprofen, had no effect on the strength of leukotriene-induced contraction. In addition, the effects of three mammalian LTD4 receptor antagonists, L-649,923, L-648,051, and LY171883 were tested. All three antagonists failed to block LTC4-simulated contraction, but were effective blockers of LTD4. LTE4-stimulated contractions were significantly blunted by all three antagonists, but the extent of blockade was less than for LTD4. Significant bioconversion of [3H]LTC4 to LTD4 and LTE4 occurred in minced lung preparations but not in lung strips. Peptide leukotrienes caused contraction in amphibian lung, though the order of potency differs from mammals. Like mammals, frogs appear to have two classes of leukotriene receptors, one for LTC4 and one for LTD4–LTE4. These results support the hypothesis that leukotriene receptors have been highly conserved through evolution, despite the fact that the nature of tissue responsiveness to leukotrienes has changed over evolutionary time.Key words: leukotrienes, bullfrogs, receptor antagonists, lung contractility, eicosanoids.
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Herman, C. A., G. A. Charlton und R. L. Cranfill. „Metabolism and cardiovascular effects of leukotrienes in warm- and cold-acclimated American bullfrogs (Rana catesbeiana)“. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 260, Nr. 5 (01.05.1991): R834—R838. http://dx.doi.org/10.1152/ajpregu.1991.260.5.r834.
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Sulfidopeptide leukotrienes are important mediators in mammals, but much less is known of their metabolism and action in nonmammalian vertebrates. This study examines the cardiovascular effects of leukotrienes on blood pressure and heart rate and compares the metabolism of leukotrienes in vivo and in vitro in warm- and cold-acclimated bullfrogs. Leukotriene C4 (LTC4) is more potent than leukotriene D4 (LTD4) and leukotriene E4 (LTE4) in eliciting hypotension. The leukotrienes are more potent in warm-acclimated animals. Conversion of [3H]LTC4 to [3H]LTD4 occurs rapidly in warm-acclimated bullfrogs, with 15.2 +/- 1.7% of the [3H]LTC4 remaining at 1.5 min. Conversion is slower in vivo in cold-acclimated frogs, with 20.2 +/- 1.7% of the [3H]LTC4 remaining by 6 min. In blood taken from warm-acclimated frogs, conversion of [3H]LTC4 to [3H]LTD4 occurs more rapidly at 22 than at 5 degrees C. This pattern is similar in blood taken from cold-acclimated frogs, suggesting that no modification of gamma-glutamyl transpeptidase occurs at low temperature. [3H]LTE4 production is not observed in vivo or in vitro during the time course of the experiments. The rapid metabolism of LTC4 to LTD4 may represent an inactivation mechanism in amphibians. The cardiovascular effects of LTC4 in vivo may be much greater than current measurements indicate because of rapid conversion of LTC4 to the less potent LTD4.
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Jones, T. R., R. Young, E. Champion, L. Charette, D. Denis, A. W. Ford-Hutchinson, R. Frenette et al. „L-649,923, Sodium (βS*, γR*)-4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-γ-hydroxy-β-methylbenzenebutanoate, a selective, orally active leukotriene receptor antagonist“. Canadian Journal of Physiology and Pharmacology 64, Nr. 8 (01.08.1986): 1068–75. http://dx.doi.org/10.1139/y86-183.
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L-649,923, Sodium (βs*, γR*)-4-(3-(4-acetyi-3-hydroxy-2-propylphenoxy)propylthio)-γ-hydroxy-β-methylbenzenebutanoate is a selective and competitive inhibitor of [3H]leukotriene D4 (Ki value of 400 nM) and to a lesser extent [3H]leukotriene C4 (Ki value of 8.6 μM) binding in guinea-pig lung homogenates. Functionally, it selectively antagonized contractions of guinea pig trachea induced by leukotriene C4, D4, E4, and F4 but not those induced by acetylcholine, histamine, serotonin, prostaglandin F2α, or U-44069 (stable endoperoxide analogue). Schild plot analysis indicated a competitive inhibition of contractions of guinea-pig ileum induced by leukotriene D4 (pA2 8.1) and contractions of guinea-pig trachea induced by leukotrienes E4 and F4 (pA2 7.1 and 6.9, respectively). In contrast, contractions of guinea-pig trachea induced by leukotrienes C4 (pA2 7.2; slope 0.6) and D4 (pA2 7.2; slope 0.7) were inhibited in a noncompetitive fashion. In vivo, intravenously administered L-649,923 selectively blocked bronchoconstriction induced in anesthetized guinea pigs by leukotriene C4 and D4 (ED50 values i.v. 0.38 and 0.26 mg/kg, respectively) but not that induced by histamine, arachidonic acid, serotonin, U-44069, or acetylcholine. Following intraduodenal administration, L-649,923, blocked leukotriene D4 induced bronchoconstriction (5 and 10 mg/kg). The present findings indicate that selective antagonists, such as L-649,923, may be useful for defining the role of leukotrienes in diseases such as bronchial asthma.
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Leikauf, G. D., H. E. Claesson, C. A. Doupnik, S. Hybbinette und R. C. Grafstrom. „Cysteinyl leukotrienes enhance growth of human airway epithelial cells“. American Journal of Physiology-Lung Cellular and Molecular Physiology 259, Nr. 4 (01.10.1990): L255—L261. http://dx.doi.org/10.1152/ajplung.1990.259.4.l255.
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Epithelial inflammation may play an obligatory role in the pathogenesis of a number of chronic pulmonary diseases such as asthma or bronchitis and has been implicated during the promotion phase of multistage carcinogenesis. At sites of inflammation, bioactive lipid mediators are released and activate a wide range of pathophysiological responses including bronchospasm. Previous studies suggest that one class of inflammatory mediators, the eicosanoids, can also influence cell growth. Epithelial cell proliferation and hyperplasia are common sequelae to irritation and inflammation, and because the lung has a high capacity to produce eicosanoids, we investigated the effects of a group of these compounds, the cysteinyl leukotrienes, on growth of human airway epithelial cells. Leukotrienes were found to be mitogenic in a concentration-dependent manner and exhibit a structure-activity relationship, with leukotriene C4 being more potent than its sequential metabolites leukotriene D4 and E4. The potency of leukotriene C4 is striking, stimulating colony-forming efficiency in concentrations as low as 10 fM. These findings suggest a new physiological role for leukotrienes in the lung that links inflammation with epithelial cell proliferation.
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Rola-Pleszczynski, Marek, und Jana Stankova. „Cytokine-Leukotriene Receptor Interactions“. Scientific World JOURNAL 7 (2007): 1348–58. http://dx.doi.org/10.1100/tsw.2007.183.
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Biochemical and pharmacological studies have identified the structure of leukotrienes, the pathways that lead to their synthesis, and the signaling events they trigger when they interact with their cognate receptors. A privileged interaction exists between these lipid mediators and another group of molecules essential for inflammation and immune modulation, namely, cytokines. Whereas leukotrienes can trigger the synthesis and release of selected cytokines in distinct cell populations, many cytokines can affect cellular responsiveness to leukotrienes by modulating leukotriene receptor expression. As we progressively begin to unravel these complex interactions, new areas of cell-cell communication and eventual therapeutic interventions will emerge.
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Denzlinger, C., W. Tetzloff, HH Gerhartz, R. Pokorny, S. Sagebiel, C. Haberl und W. Wilmanns. „Differential activation of the endogenous leukotriene biosynthesis by two different preparations of granulocyte-macrophage colony-stimulating factor in healthy volunteers“. Blood 81, Nr. 8 (15.04.1993): 2007–13. http://dx.doi.org/10.1182/blood.v81.8.2007.2007.
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Abstract Results from in vitro investigations and recent data obtained in patients with drug-induced cytopenia or myelodysplasia suggest that leukotrienes may be involved in mediating some of the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, the possible role of leukotrienes was further characterized in 21 healthy individuals to avoid modification of response to GM-CSF by disease-specific variables. The effects of two different preparations of human recombinant GM-CSF, ie, glycosylated GM- CSF as expressed in a Chinese hamster ovary carcinoma (CHO) cell line and nonglycosylated GM-CSF obtained from Escherichia coli, were compared. GM-CSF was administered subcutaneously at a single dose of 0.7 nmol/kg body weight. Pharmacokinetic parameters and hematopoietic and adverse effects were monitored by blood analyses or physical examination, respectively. Leukotriene generation in vivo was evaluated by determination of leukotriene E4 and N-acetyl-leukotriene E4 in urine. After the injection of GM-CSF from E coli, serum concentrations increased and decreased more rapidly and reached a 2.3-fold higher maximum compared with GM-CSF from CHO. GM-CSF induced a biphasic change in leukocyte counts that proceeded considerably faster after the E coli preparation than after GM-CSF from CHO. The urinary leukotriene concentration increased 1.3- to 14-fold or 2.1- to 44-fold after the administration of GM-CSF from CHO or E coli, respectively. Urinary leukotriene concentrations correlated significantly with the maximum of basophil counts and correlated with the occurrence of some adverse reactions, ie, flu-like symptoms, bone pain, or dyspnoea. Our data confirm the conception that leukotrienes may play a significant role in GM-CSF action in vivo. They especially direct attention to the possible relevance of leukotrienes to untoward effects of GM-CSF treatment.
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Denzlinger, C., W. Tetzloff, HH Gerhartz, R. Pokorny, S. Sagebiel, C. Haberl und W. Wilmanns. „Differential activation of the endogenous leukotriene biosynthesis by two different preparations of granulocyte-macrophage colony-stimulating factor in healthy volunteers“. Blood 81, Nr. 8 (15.04.1993): 2007–13. http://dx.doi.org/10.1182/blood.v81.8.2007.bloodjournal8182007.
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Results from in vitro investigations and recent data obtained in patients with drug-induced cytopenia or myelodysplasia suggest that leukotrienes may be involved in mediating some of the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, the possible role of leukotrienes was further characterized in 21 healthy individuals to avoid modification of response to GM-CSF by disease-specific variables. The effects of two different preparations of human recombinant GM-CSF, ie, glycosylated GM- CSF as expressed in a Chinese hamster ovary carcinoma (CHO) cell line and nonglycosylated GM-CSF obtained from Escherichia coli, were compared. GM-CSF was administered subcutaneously at a single dose of 0.7 nmol/kg body weight. Pharmacokinetic parameters and hematopoietic and adverse effects were monitored by blood analyses or physical examination, respectively. Leukotriene generation in vivo was evaluated by determination of leukotriene E4 and N-acetyl-leukotriene E4 in urine. After the injection of GM-CSF from E coli, serum concentrations increased and decreased more rapidly and reached a 2.3-fold higher maximum compared with GM-CSF from CHO. GM-CSF induced a biphasic change in leukocyte counts that proceeded considerably faster after the E coli preparation than after GM-CSF from CHO. The urinary leukotriene concentration increased 1.3- to 14-fold or 2.1- to 44-fold after the administration of GM-CSF from CHO or E coli, respectively. Urinary leukotriene concentrations correlated significantly with the maximum of basophil counts and correlated with the occurrence of some adverse reactions, ie, flu-like symptoms, bone pain, or dyspnoea. Our data confirm the conception that leukotrienes may play a significant role in GM-CSF action in vivo. They especially direct attention to the possible relevance of leukotrienes to untoward effects of GM-CSF treatment.
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Williams, J. D., J. L. Robin, R. A. Lewis, T. H. Lee und K. F. Austen. „Generation of leukotrienes by human monocytes pretreated with cytochalasin B and stimulated with formyl-methionyl-leucyl-phenylalanine.“ Journal of Immunology 136, Nr. 2 (15.01.1986): 642–48. http://dx.doi.org/10.4049/jimmunol.136.2.642.
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Abstract The N-formylated tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) initiated the generation of immunoreactive C-6 sulfidopeptide leukotrienes and of leukotriene B4 (LTB4) in a dose-dependent manner from monolayers of human monocytes pretreated for 10 min with 5 micrograms/ml of cytochalasin B. The EC50 for the immunoreactive C-6 sulfidopeptide leukotrienes was 10(-8) M FMLP and for immunoreactive LTB4 was 5 X 10(-8) M FMLP. The maximal response to FMLP occurred within 10 min, and the sum of the two classes of leukotrienes generated was about 1/6 that obtained from monocytes stimulated with calcium ionophore A23187. The requirement for cytochalasin B in order for FMLP, but not the calcium ionophore, to stimulate leukotriene generation is compatible with the ability of cytochalasin B to augment in other cells certain stimulus-specific transmembrane responses that are not dependent on the integrity of the cytoskeleton. Resolution by reverse phase high performance liquid chromatography of the products released from monocytes pretreated with cytochalasin B and stimulated with FMLP or calcium ionophore yielded a single peak of immunoreactive LTB4 eluting at the same retention time as the synthetic standard; immunoreactive C-6 sulfidopeptide leukotrienes eluted at the retention times of leukotriene C4 (LTC4) and leukotriene D4 (LTD4). [3H]LTB4 was not metabolically altered by monocytes pretreated with cytochalasin B and activated with FMLP in comparison with cells treated with buffer alone, whereas [3H]LTC4 was partially converted to [3H]LTD4. The leukotriene-generating response of monolayers of human monocytes pretreated with cytochalasin B to FMLP is receptor-mediated, as indicated by the inactivity of the structural analog N-acetyl-methionyl-leucyl-phenylalanine and by the capacity of the FMLP receptor antagonist carbobenzoxyphenylalanyl-methionine to inhibit the agonist action of FMLP in a dose-response fashion.
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Medeiros, Alexandra I., Anderson Sá-Nunes, Edson G. Soares, Camila M. Peres, Célio L. Silva und Lúcia H. Faccioli. „Blockade of Endogenous Leukotrienes Exacerbates Pulmonary Histoplasmosis“. Infection and Immunity 72, Nr. 3 (März 2004): 1637–44. http://dx.doi.org/10.1128/iai.72.3.1637-1644.2004.
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ABSTRACT Leukotrienes are classical mediators of inflammatory response. New aspects of leukotriene function have recently been described. We examine here the previously unreported role that leukotrienes play in the regulation of cytokines in a murine model of histoplasmosis. We demonstrate that administration of MK 886, a leukotriene synthesis inhibitor, caused Histoplasma capsulatum-infected mice to die by the day 15 of infection, whereas the correlating death rate in untreated infected mice was 0%. Treating infected animals with MK 886 inhibited leukotriene synthesis but increased leukocyte recruitment to the lungs. Subsequent to this phenomenon, levels of tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and KC chemoattractant cytokines and fungi in the lung parenchyma increased, as did inflammatory response. In contrast, IL-2, IL-5, IL-12, and gamma interferon cytokine levels actually decreased. Thus, murine response to pulmonary histoplasmosis may be leukotriene modulated. This finding may enable us to alter the course of the immune response and inflammation caused by histoplasmosis. The data from the present study suggest an important new strategy for immunologic or drug intervention in human patients.
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Fauler, Joachim, Dimitrios Tsikas, Michael Holch, Andreas Seekamp, Michael L. Nerlich, Johannes Sturm und Jürgen C. Frölich. „Enhanced urinary excretion of leukotriene E4 by patients with multiple trauma with or without adult respiratory distress syndrome“. Clinical Science 80, Nr. 5 (01.05.1991): 497–504. http://dx.doi.org/10.1042/cs0800497.
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1. The aim of the present study was to evaluate the systemic synthesis of cysteinyl leukotrienes in patients with multiple trauma. In order to do this, the urinary excretion of leukotriene E4 was assessed in the first 10 days after trauma. 2. Leukotriene E4 was unequivocally identified by g.c.-m.s. in the urine of healthy subjects and patients with multiple trauma after its conversion to 5-hydroxyeicosanoic acid. Leukotriene E4 was routinely isolated from 24 h urine samples by solid-phase extraction followed by reverse-phase h.p.l.c. and was subsequently quantified by r.i.a. 3. Healthy subjects excreted daily 10 ± 3 nmol of leukotriene E4/mol of creatinine (mean ± sem, n = 16) into urine. 4. Patients with multiple trauma who did not develop adult respiratory distress syndrome (n = 7) excreted 76.8 ± 6.7 nmol of leukotriene E4/mol of creatinine (mean ± sem) daily during the first 10 days after trauma, which was significantly (P < 0.01) more than did healthy subjects. 5. Excretion of leukotriene E4 was even more enhanced in three patients with multiple trauma who developed adult respiratory distress syndrome. Maximal amounts of 593 ± 185 nmol of leukotriene E4/mol of creatinine (mean ± sem) were excreted on day 9 after trauma by these three patients, which corresponds to a 7.7- and a 59-fold increase in excretion of leukotriene E4 compared with patients with multiple trauma who did not develop adult respiratory distress syndrome and healthy subjects, respectively. 6. The present study demonstrates an enhanced synthesis of cysteinyl leukotrienes in patients with multiple trauma, and suggests that cysteinyl leukotrienes are involved in the inflammatory reaction that follows multiple trauma.
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Chilton, F. H. „Potential phospholipid source(s) of arachidonate used for the synthesis of leukotrienes by the human neutrophil“. Biochemical Journal 258, Nr. 2 (01.03.1989): 327–33. http://dx.doi.org/10.1042/bj2580327.
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The present study has employed two approaches to address the question of whether there are specific phospholipid sources of arachidonate used for leukotriene biosynthesis in the human neutrophil. Firstly, g.c.-m.s. analysis indicated that arachidonate was lost from all major arachidonate-containing phospholipid subclasses during cell activation with ionophore A23187. On a molar basis, the rank order of breakdown among the three major phospholipids was: 1-alk-1-enyl-2-arachidonoyl-sn-glycero-3-phosphoethanolamine greater than 1-alkyl-2-arachidonoyl-sn-3-phosphocholine greater than 1-acyl-2-arachidonyl-sn-3-phosphoinositol. Leukotrienes released into the supernatant fluid accounted for only 10-35% of the total arachidonate depletion. Phospholipid sources were also identified in labelling experiments where the specific radioactivity of arachidonate in phospholipid subclasses, as well as leukotrienes produced during cell activation, was measured. The specific radioactivity of arachidonate within 1-acyl-linked molecular species of phosphatidylcholine and phosphatidylinositol was initially high relative to the leukotrienes and decreased rapidly with stimulation. By contrast, the specific radioactivity of arachidonate in all three subclasses of phosphatidylethanolamine, 1-acyl, 1-alkyl, and 1-alk-1-enyl, was 3-5-fold below that of the leukotrienes throughout cell activation. Of the six major arachidonate-containing subclasses, only in the case of 1-O-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine did the specific radioactivity correlate well with that of leukotriene B4 and 20-hydroxyleukotriene B4. These data strongly suggest that 1-ether-linked phospholipids are an important source of arachidonate used for leukotriene biosynthesis.
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Ali, A., A. W. Ford-Hutchinson und D. W. Nicholson. „Activation of protein kinase C down-regulates leukotriene C4 synthase activity and attenuates cysteinyl leukotriene production in an eosinophilic substrain of HL-60 cells.“ Journal of Immunology 153, Nr. 2 (15.07.1994): 776–88. http://dx.doi.org/10.4049/jimmunol.153.2.776.
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Abstract An eosinophilic substrain of HL-60 cells (HL-60#7) predominantly synthesized cysteinyl leukotrienes after stimulation with the calcium ionophore A23187. Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) specifically attenuated cysteinyl leukotriene production without affecting the biosynthesis of non-cysteinyl leukotrienes. The inhibition of cysteinyl leukotriene biosynthesis was prevented only by specific PKC inhibitors (staurosporine and bisindolylmaleimide) but not by inhibitors of tyrosine kinases (genistein, tyrphostin 47, and herbimycin A), protein kinase A (KT5720), or the oxidative burst (apocynin). Similar results were obtained when LTC4 synthase enzymatic activity was measured directly in the presence of saturating concentrations of exogenously added substrates. Therefore, the inhibitory effects of PKC activation on cysteinyl leukotriene formation in intact cells was attributable to effects on the LTC4 synthase enzyme. The mechanism of inhibition of LTC4 synthase by PKC activation was determined by kinetic analysis to be noncompetitive in both eosinophil-like HL-60#7 cells and monocytic THP-1 cells. Contrary to the effect of PKC activation on cysteinyl leukotriene biosynthesis, the formation of prostaglandin E2 and thromboxane B2 was elevated twofold to threefold after PMA treatment, which was prevented by the PKC inhibitor, staurosporine. We propose a regulatory model in which PKC activation shifts the profile of eicosanoid mediators produced by eosinophils from cysteinyl leukotrienes to prostanoids.
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Mygind, N., R. Dahl und H. Bisgaard. „Leukotrienes, leukotriene receptor antagonists, and rhinitis“. Allergy 55, Nr. 5 (Mai 2000): 421–24. http://dx.doi.org/10.1034/j.1398-9995.2000.00113.x.
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Freedman, Stephen M., John L. Wallace und Eldon A. Shaffer. „Characterization of leukotriene-induced contraction of the guinea-pig gallbladder in vitro“. Canadian Journal of Physiology and Pharmacology 71, Nr. 2 (01.02.1993): 145–50. http://dx.doi.org/10.1139/y93-020.
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Metabolites of arachidonic acid like prostaglandins have an established role in the pathogenesis of gallstone formation and cholecystitis, but any contribution by leukotrienes is less clear. Leukotrienes might contribute to the disease process by contracting the inflamed and (or) obstructed gallbladder, resulting in further inflammatory damage and biliary pain. To better define the role of leukotrienes, we assessed their effects on gallbladder contracility in vitro. Both leukotriene C4 (LTC4) and D4 (LTD4) had a concentration-dependent excitatory effect on guinea-pig gallbladder smooth muscle. The LTD4-receptor antagonist MK-571 (1 μM) competitively depressed the contractile response, to both LTD4 and LTC4. The source of calcium was defined using ryanodine to deplete intracellular calcium stores and nifedipine to block extracellular entry. Ryanodine (10 μM) antagonized gallbladder contraction at low concentrations of LTD4 (10−10 and 10−9 M). Nifedipine (1 μM) had a greater inhibitory effect on the contractile response at high concentrations of LTD4 (10−8–10−6 M). LTD4-induced contractions were unaffected in tissues pretreated with the neural blocker tetrodotoxin or the muscarinic antagonist atropine. Thus, leukotrienes act directly on the gallbladder smooth muscle, causing contraction at concentrations found in models of cholecystitis, suggesting that these inflammatory mediators contribute to the symptoms and morbidity associated with gallbladder disease.Key words: gallstones, cholecystitis, guinea-pig, gallbladder, leukotriene.
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Empey, Lonnie R., Keith Walker und Richard N. Fedorak. „Indomethacin worsens and a leukotriene biosynthesis inhibitor accelerates mucosal healing in rat colitis“. Canadian Journal of Physiology and Pharmacology 70, Nr. 5 (01.05.1992): 660–68. http://dx.doi.org/10.1139/y92-084.
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The implication of leukotrienes as mediators of inflammation and recent evidence that prostaglandin analogues provide a beneficial effect during experimental colitis led to the speculation that (i) leukotrienes may be injurious and (ii) prostaglandins may be protective to colonic mucosa. Using a 2% acetic acid induced rat colitis model, we administered specific cyclooxygenase (indomethacin) and leukotriene biosynthesis inhibitors (MK-886) to examine the effect of endogenous prostaglandins and leukotrienes on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, net in vivo intestinal fluid absorption, and colonic PGE2 and LTB4 levels as measured by in vivo rectal dialysis. Indomethacin treatment prior to induction of colitis reduced endogenous mucosal PGE2 levels and exacerbated macroscopic ulceration and net fluid absorption. Addition of the exogenous PGE1 analogue misoprostol to the indomethacin-exacerbated colitis completely healed colonic macroscopic ulceration and inflammation but only partially improved fluid absorptive injury. The specific leukotriene biosynthesis inhibitor MK-886 administered prior to induction of colitis healed macroscopic ulceration and inflammation but not fluid absorptive injury. This mucosal reparative effect of MK-886 occurred at a dose that reduced colonic LTB4 synthesis while concomitantly enhancing PGE2 levels. Combining MK-886 with misoprostol treatment improved not only macroscopic ulceration and inflammation but also provided a synergistic effect that maintained net colonic fluid absorption at noncolitic control levels. These studies suggest that, during the induction of experimental colitis, endogenous prostaglandins play a pivotal role in providing a mucosal healing effect, and that leukotriene biosynthesis inhibitor may manifest part of its beneficial effect by shifting arachidonic acid metabolism towards production of prostaglandins.Key words: cyclooxygenase, eicosanoids, indomethacin, inflammatory bowel disease, leukotrienes, lipoxygenase, MK-886, misoprostol, prostaglandins.
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Jackson, Sarah E., John W. Holloway, Jane A. Warner und Anthony P. Sampson. „Interleukin-13, but Not Indomethacin, Increases Cysteinyl-Leukotriene Synthesis in Human Lung Macrophages“. Journal of Allergy 2012 (29.10.2012): 1–6. http://dx.doi.org/10.1155/2012/348741.
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Aspirin-exacerbated respiratory disease (AERD) is associated with constitutively elevated synthesis of bronchoconstrictor cysteinyl-leukotrienes, associated with increased expression of leukotriene (LT)C4 synthase and Th2 cytokines and airway eosinophilia. We examined whether interleukin-13 can increase LTC4 synthase gene transcription and cysteinyl-leukotriene synthesis in macrophages isolated from resected human lung tissue and whether an NSAID (indomethacin) can trigger further cysteinyl-leukotriene synthesis in these cells. Overnight culture of human lung macrophages with IL-13 (10 ng/mL) increased spontaneous and ionophore-stimulated production of cysteinyl-leukotrienes by 42% (P=0.02) and 52% (P=0.005), respectively, as quantified by enzyme immunoassays, but PCR gene transcription assays did not demonstrate an effect on LTC4S mRNA. The addition of indomethacin (100 μM) did not modulate cysteinyl-leukotriene production in either IL-13-treated or untreated macrophages. We conclude that while IL-13 enhances cysteinyl-leukotriene synthesis in human lung macrophages, it does not replicate the enhanced LTC4 synthase expression observed in the AERD lung nor confer sensitivity to NSAIDs.
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Mansour, Mahmoud, Nabil Farouk, Abbas El Maragy, Ibrahim Radwan und Omar El-Ahmady. „Elevated Plasma Level of Leukotrienes in Bronchial Asthma Patients: A Possible Clinical Relevance“. Disease Markers 12, Nr. 2 (1994): 117–22. http://dx.doi.org/10.1155/1994/121453.
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Plasma from bronchial asthma patients and healthy controls was investigated for the content of lipoxygenase products. After lipid extraction using SEP-PAK C18Cartridges, the lipoxygenase products were measured by Enzyme-Immunoassay. Elevated chemotactic B4 was found in plasma from asthmatic patients with mean value (483±75) pmoUL, while the mean value in normal healthy donors was (140± 12.1) pmol/L (M±SE). The levels of spasmogenic cysteinyl containing leukotrienes were also very high in the bronchial asthma patients. Elevations of leukotriene B4and cysteinyl containing leukotrienes were detected during attacks of bronchial asthma. These results suggest that leukotriene B4 may be important in the pathogenesis of bronchial asthma and confirmed that peptidoleukotrienes playa role as chemical mediators during the asthmatic attack.
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Mancuso, Peter, Patrick Nana-Sinkam und Marc Peters-Golden. „Leukotriene B4 Augments Neutrophil Phagocytosis of Klebsiella pneumoniae“. Infection and Immunity 69, Nr. 4 (01.04.2001): 2011–16. http://dx.doi.org/10.1128/iai.69.4.2011-2016.2001.
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ABSTRACT Neutrophils play a critical role in the clearance of bacteria from the lung and other organs by their capacity for phagocytosis and killing. Previously, we identified an important role for the leukotrienes in rat alveolar macrophage phagocytosis ofKlebsiella pneumoniae. In this report, we explored the possibility that the leukotrienes play an important role in phagocytosis by neutrophils as well. Inhibition of endogenous leukotriene synthesis by 5-lipoxygenase knockout in mice or by pharmacologic means in human peripheral blood neutrophils attenuated phagocytosis of opsonized K. pneumoniae. Reduced phagocytosis was also observed in human neutrophils pretreated with a leukotriene B4 receptor but not a cysteinyl-leukotriene receptor antagonist. While leukotriene B4 reconstituted defective phagocytosis in leukotriene-deficient neutrophils and enhanced phagocytosis in neutrophils capable of leukotriene synthesis, leukotriene C4, leukotriene D4, 5-hydroperoxyeicosatetraenoic acid, and 5-oxo-eicosatetraenoic acid were ineffective. To determine the opsonin dependence of the leukotriene B4 augmentation of phagocytosis, we assessed the ability of leukotriene B4 to modulate neutrophil phagocytosis and the adherence of sheep erythrocytes opsonized with immunoglobulin G or the complement fragment C3bi. While leukotriene B4 augmented both Fc receptor- and complement receptor-mediated phagocytosis, increased adherence to leukotriene B4-treated neutrophils was limited to complement opsonized targets. In conclusion, we have identified a novel role for leukotriene B4 in the augmentation of neutrophil phagocytosis mediated by either the Fc or complement receptor.
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Spurney, R. F., S. Ibrahim, D. Butterly, P. E. Klotman, F. Sanfilippo und T. M. Coffman. „Leukotrienes in renal transplant rejection in rats. Distinct roles for leukotriene B4 and peptidoleukotrienes in the pathogenesis of allograft injury.“ Journal of Immunology 152, Nr. 2 (15.01.1994): 867–76. http://dx.doi.org/10.4049/jimmunol.152.2.867.
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Abstract To investigate the role of leukotrienes in renal allograft rejection, we studied the effects of specific leukotriene inhibitors in a rat kidney transplant model. The enhanced renal production of leukotrienes observed in allograft recipients was reduced in a dose-dependent manner by the specific 5-lipoxygenase inhibitor MK886. This suppression of leukotriene production caused a substantial improvement in renal function. Inhibition of 5-lipoxygenase also reduced the severity of vascular inflammation and endothelial injury in allografts, and profoundly inhibited expression of donor MHC class II Ag on kidney cells. Survival of renal allograft recipients was prolonged from 10 +/- 1 days in controls to 16 +/- 1 days in animals that received a 6-day course of MK886 (p < 0.05). To investigate the relative roles of LTB4 compared to peptidoleukotrienes in these processes, we treated a separate group of animals with the specific peptidoleukotriene receptor antagonist SKF106203. This agent inhibits the interaction of peptidoleukotrienes with their receptor(s) but does not affect the biologic actions of LTB4. In these studies, SKF106203 caused a modest improvement in renal allograft function that was of lesser magnitude than that seen with the 5-lipoxygenase inhibitor. SKF106203 also reduced vascular inflammation in allografts, but had no effect on expression of MHC class II Ag. We conclude that leukotrienes play a key role in the pathogenesis of renal allograft rejection. Furthermore, the detrimental effects of leukotrienes in rejection are mediated by distinct actions of LTB4 and peptidoleukotrienes.
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Draber, Petr, Tomas Paulenda, Pavol Utekal, Ivana Halova, Ladislav Kuchar, Ondrej Kuda, Petra Vavrova et al. „Production of leukotriene signaling mediators is limited by ORMDL3/serine palmitoyltransferase/5-lipoxygenase crosstalk“. Journal of Immunology 204, Nr. 1_Supplement (01.05.2020): 152.18. http://dx.doi.org/10.4049/jimmunol.204.supp.152.18.
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Abstract Leukotrienes and sphingolipids are critical lipid mediators participating in cellular signal transduction and development of various diseases. Metabolic pathways initiating production of these lipid mediators involve 5-lipoxygenase (5-LO)-mediated conversion of arachidonic acid to leukotrienes and serine palmitoyltransferase (SPT) de novo synthesis of sphingolipids. Previous studies showed that endoplasmic reticulum membrane protein ORMDL3 inhibits the activity of SPT and sphingolipid synthesis. However, the role of ORMDL3 in synthesis of leukotrienes is not known. In this study, we used peritoneal-derived mast cells (PDMCs) isolated from mice with ORMDL3 knockout (KO) or control mice and examined their properties. We found that PDMCs with ORMDL3 KO exhibited increased calcium response and ß-glucuronidase release when activated with antigen. These events were accompanied by increased phosphorylation of IκB-α and TNF-α production. Lipid analysis showed that ORMDL3-deficient cells exhibited not only enhanced production of sphingolipids, but also increased production of leukotriene inflammatory mediators, such as LTB4 and LTC4. These data were supported by the finding that ORMDL3 physically interacts with 5-LO. Further studies showed that 5-LO interacts with the SPT long-chain (LC)1 and SPTLC2 subunits and decreases the ceramide levels. In line with these findings, 5-LO knockdown increased the ceramide levels, and silencing of SPTLC1 decreased transition of arachidonic acid to leukotrienes. These results demonstrate physical and functional crosstalk between leukotriene and sphingolipid metabolism pathways leading to production of lipid signaling mediators.
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Hirata, K., K. Maghni, P. Borgeat und P. Sirois. „Guinea pig alveolar eosinophils and macrophages produce leukotriene B4 but no peptido-leukotriene.“ Journal of Immunology 144, Nr. 5 (01.03.1990): 1880–85. http://dx.doi.org/10.4049/jimmunol.144.5.1880.
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Abstract The metabolism of arachidonic acid (AA) was investigated in purified guinea pig alveolar eosinophils and macrophages. Alveolar eosinophils produced 12S-hydroxy-5,8,10-heptadecatraenoic acid (HHT) and small amounts only of 5-lipoxygenase products when stimulated by AA (10 microM) or ionophore A23187 (2 microM). However, when the cell suspensions were stimulated with both AA and A23187, the cells produced HHT, leukotriene (LT) B4, and 5S-hydroxy-6,8,11,14-eicosatetraenoic acid, whereas LTC4, D4, and E4 were undetectable. Similarly, alveolar macrophages stimulated with A23187 produced HHT, 5-hydroxy-6,8,11,14-eicosatetraenoic acid, and LTB4 but no peptido-leukotrienes. When LTA4 was added to suspensions of eosinophils and macrophages, only LTB4 was formed, whereas in parallel experiments, intact human platelets incubated with LTA4 produced LTC4. These data suggest that guinea pig alveolar eosinophils and macrophages contain both cyclooxygenase and 5-lipoxygenase, but do not produce peptido-leukotrienes, probably lacking LTA4 glutathione transferase activity. These studies demonstrate that guinea pig eosinophils differ from eosinophils of other animal species which have been shown to be major sources of leukotriene C4. The present data imply that eosinophils and macrophages are not the source of peptido-leukotrienes in anaphylactic guinea pig lungs.
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Runarsson, Gudmundur, Anquan Liu, Yilmaz Mahshid, Stina Feltenmark, Annika Pettersson, Eva Klein, Magnus Björkholm und Hans-Erik Claesson. „Leukotriene B4 plays a pivotal role in CD40-dependent activation of chronic B lymphocytic leukemia cells“. Blood 105, Nr. 3 (01.02.2005): 1274–79. http://dx.doi.org/10.1182/blood-2004-07-2546.
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AbstractBiosynthesis of leukotrienes (LTs) occurs in human myeloid cells and B lymphocytes. However, the function of leukotrienes in B lymphocytes is unclear. Here, we report that B-cell chronic lymphocytic leukemia (B-CLL) cells produce leukotriene B4, and that specific leukotriene biosynthesis inhibitors counteracted CD40-dependent activation of B-CLL cells. Studies on the expression of the high-affinity receptor for LTB4 (BLT1) by flow cytometry analysis showed that the receptor was expressed, to a varying degree, in all investigated B-CLL clones. At a concentration of 100 nM, the drugs BWA4C (a specific 5-lipoxygenase inhibitor) and MK-886 (a specific 5-lipoxygenase activating protein inhibitor) markedly inhibited CD40-induced DNA synthesis (45% and 38%, respectively) and CD40-induced expression of CD23, CD54, and CD150. Addition of exogenous LTB4 (150 nM) almost completely reversed the effect of the inhibitors on DNA synthesis and antigen expression. Taken together, the results of the present study suggest that leukotriene biosynthesis inhibitors may have a therapeutic role in B-CLL.
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Kiwak, Kevin J., Michael A. Moskowitz und Lawrence Levine. „Leukotriene production in gerbil brain after ischemic insult, subarachnoid hemorrhage, and concussive injury“. Journal of Neurosurgery 62, Nr. 6 (Juni 1985): 865–69. http://dx.doi.org/10.3171/jns.1985.62.6.0865.
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✓ A leukotriene-like immunoreactivity was measured by radioimmunoassay in the gerbil forebrain following ischemia and reperfusion, subarachnoid hemorrhage (SAH), or nonlethal concussive brain injury. In each paradigm an increase in immunoreactivity levels was found. Peak levels were reached 15 to 30 minutes after each insult, and slowly returned to baseline over the next 24 hours. The study supports the suggestion that cerebral vessels and circulating blood are capable of producing leukotrienes, and that a major source of production is a nonvascular component within gray matter, possibly the cortical neuron. Leukotrienes may play a role in the pathophysiology of cerebral edema formation, cerebral vasospasm, seizure activity, and other central nervous system abnormalities. These studies are the first to demonstrate leukotriene production in gerbil brain following SAH or concussive brain injury.
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Riccioni, Graziano, und Magnus Bäck. „Leukotrienes as Modifiers of Preclinical Atherosclerosis?“ Scientific World Journal 2012 (2012): 1–6. http://dx.doi.org/10.1100/2012/490968.
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Preclinical atherosclerosis represents a crucial period associated with several pathophysiological reactions in the vascular wall. Failure to diagnose preclinical atherosclerosis at this stage misses a major opportunity to prevent the long-term consequences of this disease. Surrogate biological and structural vascular markers are available to determine the presence and the extension of preclinical vascular injury in the general population. Examples of surrogate markers are carotid intima media thickness and biomarkers including high-sensitivity C-reactive protein, cell adhesion molecules and matrix metalloproteinases, and leukotrienes. Recently, leukotrienes have been implicated as mediators, biomarkers, and possible therapeutic targets in the context of subclinical atherosclerosis. The aim of this short paper is to focus on the relation between preclinical atherosclerosis and leukotrienes, with particular attention to the recent development on the use of leukotriene modifiers in the treatment of atherosclerosis.
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ZHANG, Ying-Yi, Jennifer L. WALKER, Annong HUANG, John F. KEANEY, Clary B. CLISH, Charles N. SERHAN und Joseph LOSCALZO. „Expression of 5-lipoxygenase in pulmonary artery endothelial cells“. Biochemical Journal 361, Nr. 2 (08.01.2002): 267–76. http://dx.doi.org/10.1042/bj3610267.
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Increased expression of 5-lipoxygenase (5LO) in pulmonary artery endothelial cells (PAECs) has been observed in disease states such as pulmonary hypertension and allergen challenge. To understand the function of endothelial 5LO, we examined the expression of this enzyme in normally cultured human PAECs and its characteristics when overexpressed. A small amount of 5LO message and protein was detected by reverse-transcriptase-mediated PCR (RT—PCR) and Western blotting in PAECs. Sequencing of the RT—PCR products that overlapped the entire coding region of 5LO mRNA indicated that the sequence of PAEC 5LO was identical with that of leucocyte 5LO. Incubation of the PAECs with A23187 and arachidonic acid led to a small production of 5-hydroxyeicosatetraenoic acid (5-HETE) (46–98pmol/4×106 cells) but no leukotrienes. Overexpression of 5LO in PAECs by adenovirus-mediated gene transfer revealed that the enzyme was localized in the nucleus. Incubation of the transduced cells with A23187 (5μM) caused the production of both 5LO products and downstream leukotrienes. The proportions of the produced leukotriene A4 (LTA4) hydrolates (sum of 6-trans-LTB4 and 12-epi-6-trans-LTB4), LTB4 and cysteinyl leukotriene were approx. 17:14:10. cGMP production in the 5LO-transduced PAECs was decreased by 33±14% on stimulation with A23187. These results show that cultured PAECs express a minimal amount of 5LO, which can generate some 5-HETE, but not leukotrienes. However, increased expression of 5LO in PAECs can lead to the production of all downstream leukotrienes, which could potentially cause endothelial dysfunction in the pulmonary vasculature.
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Bautz, Frank, Claudio Denzlinger, Lothar Kanz und Robert Möhle. „Chemotaxis and transendothelial migration of CD34+hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1“. Blood 97, Nr. 11 (01.06.2001): 3433–40. http://dx.doi.org/10.1182/blood.v97.11.3433.
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Recent studies suggest that bone marrow (BM)–derived chemotactic mediators such as chemokines play key roles in hematopoietic stem cell trafficking. Lipid mediators, particularly leukotrienes, are involved in leukocyte chemotaxis during inflammation but have also been detected in the normal BM. Therefore, the effects of leukotrienes on hematopoietic progenitor cells were analyzed. Cysteinyl leukotrienes, particularly leukotriene D4 (LTD4), induced strong intracellular calcium fluxes and actin polymerization in mobilized and BM CD34+ progenitors. Chemotaxis and in vitro transendothelial migration of CD34+ and more primitive CD34+/CD38− cells were 2-fold increased by LTD4 at an optimum concentration of 25 to 50 nM. Accordingly, CD34+ cells expressed the 7-transmembrane LTD4 receptor CysLT1 by reverse transcriptase–polymerase chain reaction and Western blot. Effects of LTD4 were suppressed by the CysLT1 receptor antagonist MK-571 and reduced by pertussis toxin. In contrast, LTB4 induced strong responses only in mature granulocytes. LTD4-induced calcium fluxes were also observed in granulocytes but were not reduced by MK-571, suggesting that these effects were mediated by other receptors (eg, CysLT2) rather than by CysLT1. In addition, expression of 5-lipoxygenase, the key enzyme of leukotriene biosynthesis, was detected in both hematopoietic progenitor cells and mature leukocytes. The study concludes that the functionally active LTD4 receptor CysLT1 is preferentially expressed in immature hematopoietic progenitor cells. LTD4 released in the BM might regulate progenitor cell trafficking and could also act as an autocrine mediator of hematopoiesis. This would be a first physiologic effect of cysteinyl leukotrienes apart from the many known pathophysiologic actions related to allergy and inflammation.
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Mizernitskiy, Yu L., und A. I. Petrova. „Montelukast: results and prospects for applications in pediatric practice“. Meditsinskiy sovet = Medical Council, Nr. 1 (26.02.2024): 82–88. http://dx.doi.org/10.21518/ms2024-026.
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The Centers for Disease Control and Prevention reports that more than 4 million children have been diagnosed with asthma. Currently, there is no treatment that could prevent the development of asthma or change its natural course over long-term follow-up. However, the disease can be controlled using treatments used in clinical practice. For persistent asthma in children aged 5 years and younger, low doses of inhaled glucocorticosteroids are recommended, as well as the administration of montelukast, a leukotriene receptor antagonist. In addition, montelukast is prescribed to patients with allergic rhinitis as an alternative to or in combination with oral antihistamines or nasal corticosteroids. Leukotrienes are lipid mediators that play a key role in acute and chronic inflammation and allergic diseases. They exhibit their biological effects by binding to specific G-protein-coupled receptors. Each subtype of the leukotriene receptor has unique functions and expression patterns. Leukotrienes play an important role in various allergic diseases, including bronchial asthma and allergic rhinitis. Montelukast is a cysteinyl leukotriene receptor-1 antagonist widely used to suppress the inflammatory response in asthma and allergic rhinitis. This review briefly summarizes the biology of leukotrienes and their receptors, recent developments in the field of antileukotriene drugs and the prospects for their different therapeutic applications. The role of antileukotriene drugs and key indications for the use of montelukast in the complex therapy of asthma and allergic rhinitis in children have been determined.
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Soifer, S. J., R. D. Loitz, C. Roman und M. A. Heymann. „Leukotriene end organ antagonists increase pulmonary blood flow in fetal lambs“. American Journal of Physiology-Heart and Circulatory Physiology 249, Nr. 3 (01.09.1985): H570—H576. http://dx.doi.org/10.1152/ajpheart.1985.249.3.h570.
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The factors responsible for maintaining the normally low pulmonary blood flow and high pulmonary vascular resistance in the fetus are not well understood. Since leukotrienes are potent pulmonary vasoconstrictors in many adult animal species, we determined whether leukotrienes were perhaps involved in the control of the fetal pulmonary circulation by studying the effects of putative leukotriene end organ antagonists in two groups of fetal lambs. In six fetal lambs studied at 130-134 days gestation, FPL 55712 increased pulmonary blood flow by 61% (P less than 0.05) and reduced pulmonary vascular resistance by 45% (P less than 0.05). There was a small increase in heart rate but no changes in pulmonary and systemic arterial pressures and systemic arterial blood gases. In six other fetal lambs studied at 130-140 days gestation, FPL 57231 increased pulmonary blood flow by 580% (P less than 0.05) and decreased pulmonary vascular resistance by 87% (P less than 0.05). Pulmonary and systemic arterial pressures decreased (P less than 0.05), and heart rate increased (P less than 0.05). Leukotriene end organ antagonism significantly increases fetal pulmonary blood flow and decreases pulmonary vascular resistance. Leukotrienes may play a role in the physiological control of the fetal pulmonary circulation.
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Cassin, S., K. R. Stenmark, G. Gause, L. M. Zapp, H. Kuck und J. Y. Westcott. „Leukotrienes and prostaglandins in fetal lung liquid“. Journal of Applied Physiology 68, Nr. 5 (01.05.1990): 2214–22. http://dx.doi.org/10.1152/jappl.1990.68.5.2214.
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Several recent studies have suggested that peptidoleukotrienes are involved in or responsible for the pulmonary pressor response to hypoxia as well as the normally high pulmonary vascular resistance of fetal lambs. The present studies were carried out to test these hypotheses. Fetal lambs were prepared with indwelling vascular catheters and tracheal catheters for access to lung liquid. We measured lung liquid levels of leukotrienes C4 (LTC4) and D4 (LTD4) in control unanesthetized fetal lambs with blood gases and pH in the normal range. In the control series, LTC4 and LTD4 were either not detectable or their levels were close to the limit of resolution (LTC4, less than 80 pg/ml; LTD4, less than 50 pg/ml) of the techniques utilized. Leukotriene E4 was measured in a separate study by using pooled samples, and it was also found to be below the detection limit of that assay (10 pg/ml). In a second series of animals, a level of acute hypoxia was induced to decrease fetal arterial PO2 to 12 Torr for 20 min. After hypoxia, tracheal fluid levels of leukotrienes were again below detection limits of the assays used (LTC4, less than 80 pg/ml; LTD4, less than 142 pg/ml). In another study, methodology was altered to lower the detection limits of leukotrienes in lung fluid and to allow the measurement of total peptidoleukotriene concentrations. In this study, even when hypoxia was extended for up to 1 h, leukotriene levels were consistently below the limit of detection of the assay (less than 20 pg/ml for the sum of all leukotrienes).(ABSTRACT TRUNCATED AT 250 WORDS)
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Ford-Hutchinson, A. W., P. Tagari, S. V. Ching, C. A. Anderson, J. B. Coleman und C. P. Peter. „Chronic leukotriene inhibition in the rat fails to modify the toxicological effects of a cyclooxygenase inhibitor“. Canadian Journal of Physiology and Pharmacology 71, Nr. 10-11 (01.10.1993): 806–10. http://dx.doi.org/10.1139/y93-120.
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A 5-week study was carried out in rats using a leukotriene biosynthesis inhibitor (MK-886; 3-[1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid) at a dose of 300 mg∙kg−1∙day−1, this being sufficient to produce > 90% inhibition of ex vivo leukotriene B4 synthesis in rat blood, and a cyclooxygenase inhibitor (indomethacin, 4 and 6 mg∙kg−1∙day−1) to ascertain whether inhibition of leukotriene biosynthesis would potentiate or inhibit the toxicity associated with the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), in particular the gastrointestinal damage. Treatment with indomethacin alone or in combination with MK-886 resulted in the toxicity normally associated with NSAIDs, including gastrointestinal lesions. No toxicity was associated with the administration of MK-886 alone, and MK-886 had no significant effect on the incidence of gastrointestinal lesions produced by indomethacin. These results indicate that leukotrienes are not significant mediators of NSAID-induced gastroenteropathy in the rat.Key words: nonsteroidal anti-inflammatory drugs, gastric damage, gastropathy, leukotrienes, prostaglandins.
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Claesson, Hans-Erik, Gudmundur Runarsson, Anquan Liu, Yilmaz Mahshid, Stina Feltenmark, Eva Klein und Magnus Bjorkholm. „Leukotriene B4 Plays a Pivotal Role in CD40 Dependent Activation of Chronic B Lymphocytic Leukemia Cells.“ Blood 104, Nr. 11 (16.11.2004): 4808. http://dx.doi.org/10.1182/blood.v104.11.4808.4808.
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Abstract Biosynthesis of leukotrienes occurs in human myeloid cells and B lymphocytes. However, the function of leukotrienes in B lymphocytes is unclear. Here we report that B-cell chronic lymphocytic leukemia (B-CLL) cells produce leukotriene (LT) B4 and that specific leukotriene biosynthesis inhibitors counteracted CD40-dependent activation of B-CLL cells. Studies on the expression of the high affinity receptor for LTB4 (BLT1) by flow cytometry analysis showed that the receptor was expressed, to a varying degree, in all investigated B-CLL clones. The drugs BWA4C (a specific 5-lipoxygenase inhibitor) and MK-886 (a specific 5-lipoxygenase activating protein inhibitor), at a concentration of 100 nM, markedly inhibited CD40-induced DNA synthesis (45% and 38%, respectively) and CD40-induced expression of CD23, CD54 and CD150. Addition of exogenous LTB4 (150 nM) almost completely reversed the effect of the inhibitors on DNA synthesis and antigen expression. Taken together, the results of the present study suggest that leukotriene biosynthesis inhibitors may have a therapeutic role in B-CLL.
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Marschallinger, Julia, Barbara Altendorfer, Edward Rockenstein, Miriam Holztrattner, Julia Garnweidner-Raith, Nadine Pillichshammer, Iris Leister et al. „The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies“. Neurotherapeutics 17, Nr. 3 (18.02.2020): 1061–74. http://dx.doi.org/10.1007/s13311-020-00836-3.
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Abstract Dementia with Lewy bodies (DLB) represents a huge medical need as it accounts for up to 30% of all dementia cases, and there is no cure available. The underyling spectrum of pathology is complex and creates a challenge for targeted molecular therapies. We here tested the hypothesis that leukotrienes are involved in the pathology of DLB and that blocking leukotrienes through Montelukast, a leukotriene receptor antagonist and approved anti-asthmatic drug, might alleviate pathology and restore cognitive functions. Expression of 5-lipoxygenase, the rate-limiting enzyme for leukotriene production, was indeed elevated in brains with DLB. Treatment of cognitively deficient human alpha-synuclein overexpressing transgenic mice with Montelukast restored memory. Montelukast treatment resulted in modulation of beclin-1 expression, a marker for autophagy, and in a reduction in the human alpha-synulcein load in the transgenic mice. Reducing the protein aggregation load in neurodegenerative diseases might be a novel model of action of Montelukast. Moreover, this work presents leukotriene signaling as a potential drug target for DLB and shows that Montelukast might be a promising drug candidate for future DLB therapy development.
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Byrum, Robert S., Jennifer L. Goulet, Richard J. Griffiths und Beverly H. Koller. „Role of the 5-Lipoxygenase–activating Protein (FLAP) in Murine Acute Inflammatory Responses“. Journal of Experimental Medicine 185, Nr. 6 (17.03.1997): 1065–76. http://dx.doi.org/10.1084/jem.185.6.1065.
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Leukotrienes are potent inflammatory mediators synthesized from arachidonic acid (AA) predominately by cells of myeloid origin. The synthesis of these lipids is believed to be dependent not only on the expression of the enzyme 5-lipoxygenase (5-LO), which catalyzes the first steps in the synthesis of leukotrienes, but also on expression of a nuclear membrane protein termed the 5-LO–activating protein (FLAP). To study the relationship of these two proteins in mediating the production of leukotrienes in vivo and to determine whether the membrane protein FLAP has additional functions in various inflammatory processes, we have generated a mouse line deficient in this protein. FLAP-deficient mice develop normally and are healthy. However, an array of assays comparing inflammatory reactions in FLAP-deficient mice and in normal controls revealed that FLAP plays a role in a subset of these reactions. Although examination of DTH and IgE-mediated passive anaphylaxis showed no difference between wild-type and FLAP-deficient animals, mice without FLAP possessed a blunted inflammatory response to topical AA and had increased resistance to platelet-activating factor–induced shock compared to controls. Also, edema associated with Zymosan A–induced peritonitis was markedly reduced in animals lacking FLAP. To determine whether these differences relate solely to a deficit in leukotriene production, or whether they reflect an additional role for FLAP in inflammation, we compared the FLAP-deficient mice to 5-LO–deficient animals. Evaluation of mice lacking FLAP and 5-LO indicated that production of leukotrienes during inflammatory responses is dependent upon the availability of FLAP and did not support additional functions for FLAP beyond its role in leukotriene production.