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Sven-erik Dahlén - One of the best experts on this subject based on the ideXlab platform.
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leukotriene receptors version 2019 4 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Magnus Back, Jilly F. Evans, Sven-erik Dahlén, Jeffrey M. Drazen, Charles Brink, Douglas W P Hay, Motonao Nakamura, Nan Chiang, Gordon Dent, William PowellAbstract:The leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [31, 34]) are activated by the endogenous ligands Leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [189] and the vanilloid TRPV1 ligand-gated nonselective cation channel [210]. The receptors for the cysteinyl-Leukotrienes (i.e. LTC4, LTD4 and LTE4) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [34]. Cysteinyl-Leukotrienes have also been suggested to signal through the P2Y12 receptor [91, 236, 265], GPR17 [53] and GPR99 [161].
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international union of basic and clinical pharmacology lxxxiv leukotriene receptor nomenclature distribution and pathophysiological functions
Pharmacological Reviews, 2011Co-Authors: Magnus Back, Takehiko Yokomizo, Jilly F. Evans, Sven-erik Dahlén, Jeffrey M. Drazen, Charles N Serhan, Enrico G RovatiAbstract:The seven-transmembrane G protein-coupled receptors activated by Leukotrienes are divided into two subclasses based on their ligand specificity for either leukotriene B4 or the cysteinyl Leukotrienes (LTC4, LTD4, and LTE4). These receptors have been designated BLT and CysLT receptors, respectively, and a subdivision into BLT1 and BLT2 receptors and CysLT1 and CysLT2 receptors has been established. However, recent findings have also indicated the existence of putative additional leukotriene receptor subtypes. Furthermore, other ligands interact with the leukotriene receptors. Finally, Leukotrienes may also activate other receptor classes, such as purinergic receptors. The aim of this review is to provide an update on the pharmacology, expression patterns, and pathophysiological roles of the leukotriene receptors as well as the therapeutic developments in this area of research.
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saliva is one likely source of leukotriene b4 in exhaled breath condensate
European Respiratory Journal, 2006Co-Authors: Flora Gaber, Fernando Acevedo, Ingrid Delin, Brittmarie Sundblad, Lena Palmberg, Kjell Larsson, Maria Kumlin, Sven-erik DahlénAbstract:Leukotriene (LT)B4 in exhaled breath condensate (EBC) has been reported to be elevated in airway inflammation. The origin of Leukotrienes in EBC is, however, not established. The aims of this study ...
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bronchial responsiveness to leukotriene d4 is resistant to inhaled fluticasone propionate
The Journal of Allergy and Clinical Immunology, 2006Co-Authors: Par Gyllfors, Kjell Larsson, Sven-erik Dahlén, Maria Kumlin, Barbro DahlenAbstract:BACKGROUND: Inhaled corticosteroids are highly effective in asthma, reducing inflammatory markers and bronchial hyperresponsiveness. Cysteinyl-Leukotrienes are major mediators of airway obstruction and display proinflammatory effects. Although the synthesis of Leukotrienes is not affected by corticosteroid treatment, the influence of corticosteroids on the leukotriene pathway remains unresolved. OBJECTIVE: We investigated whether or not bronchial responsiveness to leukotriene (LT) D(4) is reduced by fluticasone propionate in subjects with asthma. METHODS: In 13 subjects with mild asthma, inhalation challenges with methacholine and LTD(4) were performed on consecutive days before and after 2 weeks of treatment with inhaled fluticasone 500 mug, twice daily, in a double-blind, randomized, placebo-controlled study with crossover design and 3 weeks of washout between periods. Exhaled nitric oxide was measured as a marker of corticosteroid responsiveness, and baseline urinary LTE(4) concentrations as an index of cysteinyl-leukotriene biosynthesis. RESULTS: Fluticasone produced a significant decrease in methacholine responsiveness, corresponding to 2.6-fold shift in the PD(20) FEV(1), and a significant reduction in the levels of exhaled nitric oxide. By contrast, bronchial responsiveness to LTD(4) in the same subjects was unaffected by fluticasone, as were urinary LTE(4) concentrations. CONCLUSION: These new data indicate that neither the biosynthesis nor the actions of Leukotrienes appear to be sensitive to inhaled corticosteroids. CLINICAL IMPLICATIONS: The study provides mechanistic support for the additive therapeutic efficacy of antiLeukotrienes and inhaled corticosteroids in asthma.
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effect of the leukotriene receptor antagonist mk 0679 on baseline pulmonary function in aspirin sensitive asthmatic subjects
Thorax, 1993Co-Authors: Barbro Dahlen, D J Margolskee, O Zetterstrom, Sven-erik DahlénAbstract:BACKGROUND--The cysteinyl Leukotrienes (LTC4, LTD4, and LTE4) have been shown to mediate airway obstruction evoked by several factors which trigger asthmatic reactions--for example, allergen and exercise. Accordingly, drugs which block the action or formation of these Leukotrienes are being evaluated as a new treatment of asthma. Elevated production of Leukotrienes has been reported in asthmatic subjects who are intolerant to aspirin and related nonsteroidal anti-inflammatory drugs. In this study the influence of the specific leukotriene receptor antagonist MK-0679 was tested on basal airway function in asthmatic patients with documented aspirin intolerance. METHODS--The eight subjects in the study had a mean baseline FEV1 of 78% predicted (range 58-99%) and six required treatment with inhaled glucocorticosteroids (400-1200 micrograms budesonide/beclomethasone daily). On two separate days the subjects received either 825 mg MK-0679 or placebo, orally in a double blind, randomised, crossover design. RESULTS--The leukotriene antagonist MK-0679 caused bronchodilation which lasted for at least nine hours. The average peak improvement in FEV1 was 18% above the predrug baseline, but the bronchodilator response varied between 34% and 5% and was found to correlate strongly with the severity of asthma and aspirin sensitivity. CONCLUSIONS--The findings indicate that ongoing leukotriene production may be one cause of persistent airway obstruction in aspirin sensitive asthmatic subjects and that they may benefit from treatment with a leukotriene receptor antagonist.
Brett Connolly - One of the best experts on this subject based on the ideXlab platform.
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characterization of the human cysteinyl leukotriene cyslt1 receptor
Nature, 1999Co-Authors: Kevin R Lynch, Gary P Oneill, Dongsoon Im, Nicole Sawyer, Kathleen M Metters, Nathalie Coulombe, Mark Abramovitz, David J Figueroa, Zhizhen Zeng, Brett ConnollyAbstract:The cysteinyl Leukotrienes—leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)—are important mediators of human bronchial asthma1,2,3,. Pharmacological studies have determined that cysteinyl Leukotrienes activate at least two receptors, designated CysLT1 and CysLT2 (refs 4,5,6). The CysLT1-selective antagonists, such as montelukast (Singulair)7,8,9,10, zafirlukast (Accolate)11 and pranlukast (Onon)12, are important in the treatment of asthma. Previous biochemical characterization of CysLT1 antagonists and the CysLT1 receptor has been in membrane preparations from tissues enriched for this receptor13. Here we report the molecular and pharmacological characterization of the cloned human CysLT1 receptor. We describe the functional activation (calcium mobilization) of this receptor by LTD4 and LTC4, and competition for radiolabelled LTD4 binding to this receptor by the cysteinyl Leukotrienes and three structurally distinct classes of CysLT1-receptor antagonists. We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung. In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT1-receptor gene to the X chromosome.
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characterization of the human cysteinyl leukotriene cyslt1 receptor
Nature, 1999Co-Authors: Kevin R Lynch, Gary P Oneill, Nicole Sawyer, Kathleen M Metters, Nathalie Coulombe, Mark Abramovitz, David J Figueroa, Zhizhen Zeng, Qingyun Liu, Brett ConnollyAbstract:The cysteinyl Leukotrienes-leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)-are important mediators of human bronchial asthma. Pharmacological studies have determined that cysteinyl Leukotrienes activate at least two receptors, designated CysLT1 and CysLT2. The CysLT1-selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), are important in the treatment of asthma. Previous biochemical characterization of CysLT1 antagonists and the CysLT1 receptor has been in membrane preparations from tissues enriched for this receptor. Here we report the molecular and pharmacological characterization of the cloned human CysLT1 receptor. We describe the functional activation (calcium mobilization) of this receptor by LTD4 and LTC4, and competition for radiolabelled LTD4 binding to this receptor by the cysteinyl Leukotrienes and three structurally distinct classes of CysLT1-receptor antagonists. We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung. In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT1-receptor gene to the X chromosome.
Kevin R Lynch - One of the best experts on this subject based on the ideXlab platform.
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characterization of the human cysteinyl leukotriene cyslt1 receptor
Nature, 1999Co-Authors: Kevin R Lynch, Gary P Oneill, Dongsoon Im, Nicole Sawyer, Kathleen M Metters, Nathalie Coulombe, Mark Abramovitz, David J Figueroa, Zhizhen Zeng, Brett ConnollyAbstract:The cysteinyl Leukotrienes—leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)—are important mediators of human bronchial asthma1,2,3,. Pharmacological studies have determined that cysteinyl Leukotrienes activate at least two receptors, designated CysLT1 and CysLT2 (refs 4,5,6). The CysLT1-selective antagonists, such as montelukast (Singulair)7,8,9,10, zafirlukast (Accolate)11 and pranlukast (Onon)12, are important in the treatment of asthma. Previous biochemical characterization of CysLT1 antagonists and the CysLT1 receptor has been in membrane preparations from tissues enriched for this receptor13. Here we report the molecular and pharmacological characterization of the cloned human CysLT1 receptor. We describe the functional activation (calcium mobilization) of this receptor by LTD4 and LTC4, and competition for radiolabelled LTD4 binding to this receptor by the cysteinyl Leukotrienes and three structurally distinct classes of CysLT1-receptor antagonists. We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung. In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT1-receptor gene to the X chromosome.
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characterization of the human cysteinyl leukotriene cyslt1 receptor
Nature, 1999Co-Authors: Kevin R Lynch, Gary P Oneill, Nicole Sawyer, Kathleen M Metters, Nathalie Coulombe, Mark Abramovitz, David J Figueroa, Zhizhen Zeng, Qingyun Liu, Brett ConnollyAbstract:The cysteinyl Leukotrienes-leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)-are important mediators of human bronchial asthma. Pharmacological studies have determined that cysteinyl Leukotrienes activate at least two receptors, designated CysLT1 and CysLT2. The CysLT1-selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), are important in the treatment of asthma. Previous biochemical characterization of CysLT1 antagonists and the CysLT1 receptor has been in membrane preparations from tissues enriched for this receptor. Here we report the molecular and pharmacological characterization of the cloned human CysLT1 receptor. We describe the functional activation (calcium mobilization) of this receptor by LTD4 and LTC4, and competition for radiolabelled LTD4 binding to this receptor by the cysteinyl Leukotrienes and three structurally distinct classes of CysLT1-receptor antagonists. We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung. In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT1-receptor gene to the X chromosome.
Jesper Z. Haeggström - One of the best experts on this subject based on the ideXlab platform.
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Leukotriene A4 Hydrolase and Leukotriene C4 Synthase
Lipoxygenases in Inflammation, 2016Co-Authors: Agnes Rinaldo-matthis, Jesper Z. HaeggströmAbstract:Leukotrienes are potent proinflammatory and immune modulating lipid mediators synthesized along the 5-lipoxygenase pathway of arachidonic acid metabolism. Leukotriene B4 is one of the most potent chemotactic agents known while leukotriene C4, D4, and E4 are a powerful smooth muscle contracting agents, particularly in the respiratory tract and microcirculation. The committed steps in the biosynthesis of leukotriene B4 and C4 are catalyzed by the key enzymes leukotriene A 4 hydrolase and leukotriene C 4 synthase, respectively. In this chapter we discuss the most recent advances in the understanding of these two enzymes at a structural, functional, and biological level.
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pre steady state kinetic characterization of thiolate anion formation in human leukotriene c synthase
Biochemistry, 2012Co-Authors: Agnes Rinaldomatthis, Ralf Morgenstern, Shabbir Ahmad, Anders Wetterholm, P J Lachmann, Jesper Z. HaeggströmAbstract:Human leukotriene C4 synthase (hLTC4S) is an integral membrane protein that catalyzes the committed step in the biosynthesis of cysteinyl-Leukotrienes, i.e., formation of leukotriene C4 (LTC4). Thi...
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Leukotriene A4 hydrolase.
Prostaglandins & Other Lipid Mediators, 2002Co-Authors: Jesper Z. Haeggström, Fredrik Tholander, Filippa Kull, Peter C. Rudberg, Marjolein M. G. M. ThunnissenAbstract:The Leukotrienes (LTs) are a family of lipid mediators involved in inflammation and allergy. Leukotriene B4 is a classical chemoattractant, which triggers adherence and aggregation of leukocytes to the endothelium at only nanomolar concentrations. In addition, leukotriene B4 modulates immune responses, participates in the host-defense against infections, and is a key mediator of PAF-induced lethal shock. Because of these powerful biological effects, leukotriene B4 is implicated in a variety of acute and chronic inflammatory diseases, e.g. nephritis, arthritis, dermatitis, and chronic obstructive pulmonary disease. The final step in the biosynthesis of leukotriene B4 is catalyzed by leukotriene A4 hydrolase, a unique bi-functional zinc metalloenzyme with an anion-dependent aminopeptidase activity. Here we describe the most recent developments regarding our understanding of the structure, function, and catalytic mechanisms of leukotriene A4 hydrolase.
Maria Kumlin - One of the best experts on this subject based on the ideXlab platform.
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saliva is one likely source of leukotriene b4 in exhaled breath condensate
European Respiratory Journal, 2006Co-Authors: Flora Gaber, Fernando Acevedo, Ingrid Delin, Brittmarie Sundblad, Lena Palmberg, Kjell Larsson, Maria Kumlin, Sven-erik DahlénAbstract:Leukotriene (LT)B4 in exhaled breath condensate (EBC) has been reported to be elevated in airway inflammation. The origin of Leukotrienes in EBC is, however, not established. The aims of this study ...
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bronchial responsiveness to leukotriene d4 is resistant to inhaled fluticasone propionate
The Journal of Allergy and Clinical Immunology, 2006Co-Authors: Par Gyllfors, Kjell Larsson, Sven-erik Dahlén, Maria Kumlin, Barbro DahlenAbstract:BACKGROUND: Inhaled corticosteroids are highly effective in asthma, reducing inflammatory markers and bronchial hyperresponsiveness. Cysteinyl-Leukotrienes are major mediators of airway obstruction and display proinflammatory effects. Although the synthesis of Leukotrienes is not affected by corticosteroid treatment, the influence of corticosteroids on the leukotriene pathway remains unresolved. OBJECTIVE: We investigated whether or not bronchial responsiveness to leukotriene (LT) D(4) is reduced by fluticasone propionate in subjects with asthma. METHODS: In 13 subjects with mild asthma, inhalation challenges with methacholine and LTD(4) were performed on consecutive days before and after 2 weeks of treatment with inhaled fluticasone 500 mug, twice daily, in a double-blind, randomized, placebo-controlled study with crossover design and 3 weeks of washout between periods. Exhaled nitric oxide was measured as a marker of corticosteroid responsiveness, and baseline urinary LTE(4) concentrations as an index of cysteinyl-leukotriene biosynthesis. RESULTS: Fluticasone produced a significant decrease in methacholine responsiveness, corresponding to 2.6-fold shift in the PD(20) FEV(1), and a significant reduction in the levels of exhaled nitric oxide. By contrast, bronchial responsiveness to LTD(4) in the same subjects was unaffected by fluticasone, as were urinary LTE(4) concentrations. CONCLUSION: These new data indicate that neither the biosynthesis nor the actions of Leukotrienes appear to be sensitive to inhaled corticosteroids. CLINICAL IMPLICATIONS: The study provides mechanistic support for the additive therapeutic efficacy of antiLeukotrienes and inhaled corticosteroids in asthma.
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benefits from adding the 5 lipoxygenase inhibitor zileuton to conventional therapy in aspirin intolerant asthmatics
American Journal of Respiratory and Critical Care Medicine, 1998Co-Authors: Barbro Dahlen, Maria Kumlin, E Nizankowska, Andrew Szczeklik, Olle Zetterstrom, Grazyna Bochenek, Lucyna Mastalerz, Grazyna Pinis, Linda J Swanson, Terry I BoodhooAbstract:From bronchoprovocation studies and investigations of the acute effects of drugs that inhibit Leukotrienes (LT), the hypothesis has emerged that Leukotrienes are important mediators of airway obstruction and other symptoms in aspirin-intolerant asthma (AIA). However, it has yet not been shown if subjects with AIA respond favorably to clinical treatment with leukotriene inhibitors. Therefore, in a double-blind placebo-controlled crossover study, we examined the effects of 6 wk of treatment with the leukotriene-pathway inhibitor zileuton (600 mg, four times daily) in 40 patients with well-characterized AIA. The treatment was added to existing therapy, which included medium to high doses of inhaled (average daily dose 1,030 μ g of beclomethasone or budesonide) or oral glucocorticosteroids (4 to 25 mg/d) for all but one of the patients. On top of this treated baseline, there were no significant effects of adding placebo, indicating that their asthma was kept relatively stable. However, there was an acute and ...