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Journal articles on the topic 'CysLTs'

Author: Grafiati
Published: 4 June 2021
Last updated: 6 February 2022

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1

Baptista-dos-Reis, Renata, Valdirene S. Muniz, and Josiane S. Neves. "Multifaceted Roles of Cysteinyl Leukotrienes in Eliciting Eosinophil Granule Protein Secretion." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/848762.

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Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to act via at least 2 receptors, namely, cysLT1receptor (cysLT1R) and cysLT2receptor (cysLT2R). Eosinophils, which are granulocytes classically associated with host defense against parasitic helminthes and allergic conditions, are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse preformed proteins. Human eosinophils are the main source of cysLTs and are recognized to express both cysLTs receptors (cysLTRs) on their surface, at the plasma membrane. More recently, we identified the expression of cysLTRs in eosinophil granule membranes and demonstrated that cysLTs, acting via their granule membrane-expressed receptors, elicit secretion from cell-free human eosinophil granules. Herein, we review the multifaceted roles of cysLTs in eliciting eosinophil granule protein secretion. We discuss the intracrine and autocrine/paracrine secretory responses evoked by cysLTs in eosinophils and in cell-free extracellular eosinophil crystalloid granules. We also discuss the importance of this finding in eosinophil immunobiology and speculate on its potential role(s) in eosinophilic diseases.
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2

Bandeira-Melo, Christianne, Lesley J. Woods, Mojabeng Phoofolo, and Peter F. Weller. "Intracrine Cysteinyl Leukotriene Receptor–mediated Signaling of Eosinophil Vesicular Transport–mediated Interleukin-4 Secretion." Journal of Experimental Medicine 196, no. 6 (September 16, 2002): 841–50. http://dx.doi.org/10.1084/jem.20020516.

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We investigated whether cysteinyl leukotrienes (cysLT) are intracrine signal transducers that regulate human eosinophil degranulation mechanisms. Interleukin (IL)-16, eotaxin, and RANTES stimulate vesicular transport–mediated release of preformed, granule-derived IL-4 and RANTES from eosinophils and the synthesis at intracellular lipid bodies of LTC4, the dominant 5-lipoxygenase–derived eicosanoid in eosinophils. 5-Lipoxygenase inhibitors blocked IL-16–, eotaxin-, and RANTES-induced IL-4 release; but neither exogenous LTC4, LTD4, nor LTE4 elicited IL-4 release. Only after membrane permeabilization enabled cysLTs to enter eosinophils did LTC4 and LTD4 stimulate IL-4, but not RANTES, release. LTC4-elicited IL-4 release was pertussis toxin inhibitable, but inhibitors of the two known G protein–coupled cysLT receptors (cysLTRs) (CysLT1 and CysLT2) did not block LTC4-elicited IL-4 release. LTC4 was 10-fold more potent than LTD4 and at low concentrations (0.3–3 nM) elicited, and at higher concentrations (>3 nM) inhibited, IL-4 release from permeabilized eosinophils. Likewise with intact eosinophils, LTC4 export inhibitors, which increased intracellular LTC4, inhibited eotaxin-elicited IL-4 release. Thus, LTC4 acts, via an intracellular cysLTR distinct from CysLT1 or CysLT2, as a signal transducer to selectively regulate IL-4 release. These results demonstrate that LTC4, well recognized as a paracrine mediator, may also dynamically govern inflammatory and immune responses as an intracrine mediator of eosinophil cytokine secretion.
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3

Ballerini, P., P. Di Iorio, R. Ciccarelli, F. Caciagli, A. Polp, A. Beraudi, S. Buccella, et al. "P2Y1 and Cysteinyl Leukotriene Receptors Mediate Purine and Cysteinyl Leukotriene Co-Release in Primary Cultures of Rat Microglia." International Journal of Immunopathology and Pharmacology 18, no. 2 (April 2005): 255–68. http://dx.doi.org/10.1177/039463200501800208.

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Inflammation is widely recognized as contributing to the pathology of acute and chronic neurodegenerative conditions. Microglial cells are pathologic sensors in the brain and activated microglia have been viewed as detrimental. Leukotriene, including cysteinyl leukotrienes (CysLTs) are suggested to be involved in brain inflammation and neurological diseases and ATP, by its receptors is a candidate for microglia activation. A23187 (10μM) stimulated microglia to co-release CysLTs and [3H]adenine based purines ([3H]ABPs), mainly ATP. The biosynthetic production of CysLTs was abolished by 10μM MK-886, an inhibitor of 5-lipoxygenase-activating protein activity. RT-PCR analysis showed that microglia expressed both CysLT1 / CysLT2 receptors, P2Y1 ATP-receptors and several members of the ATP binding cassette (ABC) transporters including MRP1, MRP4 and Pgp. The increase in [Ca2+]i elicited by LTD4 (0.1 μM) and 2MeSATP (100μM), agonists for CysLT- and P2Y1-receptors, was abolished by the respective antagonists, BAYu9773 (0.5 μM) and suramin (50 μM). The stimulation of both receptor subtypes, induced a concomitant increase in the release of both [3H]ABPs and CysLTs that was blocked by the antagonists and significantly reduced by a cocktail of ABC transporter inhibitors, BAPTA/AM (intracellular Ca2+ chelator) and staurosporine (0.1 μM, PKC blocker). P2Y antagonist was unable to antagonise the effects of LTD4 and BAYu9773 did not reduce the effects of 2MeSATP. These data suggest that: i) the efflux of purines and cysteinyl-leukotrienes is specifically and independently controlled by the two receptor types, ii) calcium, PKC and the ABC transporter system can reasonably be considered common mechanisms underlying the release of ABPs and CysLTs from microglia. The blockade of P2Y1 or CysLT1/CysLT2 receptors by specific antagonists that abolished the raise in [Ca2+]i and drastically reduced the concomitant efflux of both compounds, as well as the effects of BAPTA and staurosporine support this hypothesis. In conclusion, the data of the present study suggest a cross talk between the purine and leukotriene systems in a possible autocrine/paracrine control of the microglia-mediated initiation and progression of an inflammatory response.
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4

Voisin, Tiphaine, Caroline Perner, Marie-Angele Messou, Stephanie Shiers, Saltanat Ualiyeva, Yoshihide Kanaoka, Theodore J. Price, et al. "The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch." Proceedings of the National Academy of Sciences 118, no. 13 (March 22, 2021): e2022087118. http://dx.doi.org/10.1073/pnas.2022087118.

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Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2−/− mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.
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5

Steinke, John W., Spencer C. Payne, and Larry Borish. "Interleukin-4 in the Generation of the AERD Phenotype: Implications for Molecular Mechanisms Driving Therapeutic Benefit of Aspirin Desensitization." Journal of Allergy 2012 (January 3, 2012): 1–9. http://dx.doi.org/10.1155/2012/182090.

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Aspirin-exacerbated respiratory disease (AERD) is explained in part by over-expression of 5-lipoxygenase, leukotriene C4 synthase (LTC4S) and the cysteinyl leukotriene (CysLT) receptors (CysLT1 and 2), resulting in constitutive over-production of CysLTs and the hyperresponsiveness to CysLTs that occurs with aspirin ingestion. Increased levels of IL-4 have been found in the sinus mucosa and nasal polyps of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the upregulation of LTC4S by mast cells and the upregulation of CysLT1 and 2 receptors on many immune cell types. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD reflecting diminished expression of cyclooxygenase (COX)-2. IL-4 can inhibit basal and stimulated expression of COX-2 and microsomal PGE synthase 1 leading to decreased capacity for PGE2 secretion. Thus, IL-4 plays an important pathogenic role in generating the phenotype of AERD. This review will examine the evidence supporting this hypothesis and describe a model of how aspirin desensitization provides therapeutic benefit for AERD patients.
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6

Colazzo, Francesca, Paolo Gelosa, Elena Tremoli, Luigi Sironi, and Laura Castiglioni. "Role of the Cysteinyl Leukotrienes in the Pathogenesis and Progression of Cardiovascular Diseases." Mediators of Inflammation 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/2432958.

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Cysteinyl leukotrienes (CysLTs) are potent lipid inflammatory mediators synthesized from arachidonic acid, through the 5-lipoxygenase (5-LO) pathway. Owing to their properties, CysLTs play a crucial role in the pathogenesis of inflammation; therefore, CysLT modifiers as synthesis inhibitors or receptor antagonists, central in asthma management, may become a potential target for the treatment of other inflammatory diseases such as the cardiovascular disorders. 5-LO pathway activation and increased expression of its mediators and receptors are found in cardiovascular diseases. Moreover, the cardioprotective effects observed by using CysLT modifiers are promising and contribute to elucidate the link between CysLTs and cardiovascular disease. The aim of this review is to summarize the state of present research about the role of the CysLTs in the pathogenesis and progression of atherosclerosis and myocardial infarction.
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7

Theron, A. J., H. C. Steel, G. R. Tintinger, C. M. Gravett, R. Anderson, and C. Feldman. "Cysteinyl Leukotriene Receptor-1 Antagonists as Modulators of Innate Immune Cell Function." Journal of Immunology Research 2014 (2014): 1–16. http://dx.doi.org/10.1155/2014/608930.

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Cysteinyl leukotrienes (cysLTs) are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and monocytes/macrophages. Notwithstanding potent bronchoconstrictor activity, cysLTs are also proinflammatory consequent to their autocrine and paracrine interactions with G-protein-coupled receptors expressed not only on the aforementioned cell types, but also on Th2 lymphocytes, as well as structural cells, and to a lesser extent neutrophils and CD8+cells. Recognition of the involvement of cysLTs in the immunopathogenesis of various types of acute and chronic inflammatory disorders, especially bronchial asthma, prompted the development of selective cysLT receptor-1 (cysLTR1) antagonists, specifically montelukast, pranlukast, and zafirlukast. More recently these agents have also been reported to possess secondary anti-inflammatory activities, distinct from cysLTR1 antagonism, which appear to be particularly effective in targeting neutrophils and monocytes/macrophages. Underlying mechanisms include interference with cyclic nucleotide phosphodiesterases, 5′-lipoxygenase, and the proinflammatory transcription factor, nuclear factor kappa B. These and other secondary anti-inflammatory mechanisms of the commonly used cysLTR1 antagonists are the major focus of the current review, which also includes a comparison of the anti-inflammatory effects of montelukast, pranlukast, and zafirlukast on human neutrophilsin vitro, as well as an overview of both the current clinical applications of these agents and potential future applications based on preclinical and early clinical studies.
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8

Bankova, Lora G., Juying Lai, Eri Yoshimoto, Joshua A. Boyce, K. Frank Austen, Yoshihide Kanaoka, and Nora A. Barrett. "Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99." Proceedings of the National Academy of Sciences 113, no. 22 (May 16, 2016): 6242–47. http://dx.doi.org/10.1073/pnas.1605957113.

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Cysteinyl leukotrienes (cysLTs), leukotriene C4 (LTC4), LTD4, and LTE4 are proinflammatory lipid mediators with pathobiologic function in asthma. LTE4, the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma. We recently identified GPR99 as a high-affinity receptor for LTE4 that mediates cutaneous vascular permeability. Here we demonstrate that a single intranasal exposure to extract from the respiratory pathogen Alternaria alternata elicits profound epithelial cell (EpC) mucin release and submucosal swelling in the nasal mucosa of mice that depends on cysLTs, as it is absent in mice deficient in the terminal enzyme for cysLT biosynthesis, LTC4 synthase (LTC4S). These mucosal changes are associated with mast cell (MC) activation and absent in MC-deficient mice, suggesting a role for MCs in control of EpC function. Of the three CysLTRs, only GPR99-deficient mice are fully protected from EpC mucin release and swelling elicited by Alternaria or by intranasal LTE4. GPR99 expression is detected on lung and nasal EpCs, which release mucin to doses of LTE4 one log lower than that required to elicit submucosal swelling. Finally, mice deficient in MCs, LTC4S, or GPR99 have reduced baseline numbers of goblet cells, indicating an additional function in regulating EpC homeostasis. These results demonstrate a novel role for GPR99 among CysLTRs in control of respiratory EpC function and suggest that inhibition of LTE4 and of GPR99 may have therapeutic benefits in asthma.
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9

Różańska, Małgorzata, Paweł Bielecki, Joanna Reszeć, Krzysztof Kowal, and Marek Rogowski. "Cysteinyl leukotriene 1 receptor expression in nasal polyps." Otolaryngologia Polska 72, no. 5 (October 1, 2018): 1–5. http://dx.doi.org/10.5604/01.3001.0012.5422.

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Cysteinyl leukotrienes (CysLTs) have been implicated in the pathogenesis of chronic rhinosinusitis (CRS). This study was undertaken to better understand the role of CysLTs in the development of CRS through 1). assessment of the pattern of expression of CysLT1 receptor in nasal polyps from patients with CRS and 2). correlation of expression of CysLT1 receptor with clinical features. Expression of CysLT1 receptor was evaluated immunohistochemically in nasal polyps from 20 patients with CRS and nasal mucosa from 10 control subject undergoing plastic surgery of the nose. Patients with CRS showed significantly higher expression of CysLT1 receptor as compared with the control group (p<0.05). The expression of CysLT1 receptor in sub-epithelial inflammatory infiltrates tended to be higher in patients with CRS and allergy as compared with patients with CRS but without allergy (p=0.07). In particular, the expression of CysLT1 receptor in sub-epithelial inflammatory infiltrates was significantly greater in 3 patients with CRS and drug allergy as compared with patients with CRS but without drug allergy (p=0.03). Increased expression of CysLT1 receptor in inflamed mucosa of nasal polyps in patients with allergy might suggest particular role of CysLTs in the pathogenesis of nasal polyps in this group of patients.
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10

Sasaki, Fumiyuki, and Takehiko Yokomizo. "The leukotriene receptors as therapeutic targets of inflammatory diseases." International Immunology 31, no. 9 (May 28, 2019): 607–15. http://dx.doi.org/10.1093/intimm/dxz044.

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Abstract Leukotrienes (LTs) are inflammatory mediators derived from arachidonic acid. LTs include the di-hydroxy acid LT (LTB4) and the cysteinyl LTs (CysLTs; LTC4, LTD4 and LTE4), all of which are involved in both acute and chronic inflammation. We and other groups identified a high-affinity LTB4 receptor, BLT1; the LTC4 and LTD4 receptors, CysLT1 and CysLT2; and the LTE4 receptor, GPR99. Pharmacological studies have shown that BLT1 signaling stimulates degranulation, chemotaxis and phagocytosis of neutrophils, whereas CysLT1 and CysLT2 signaling induces airway inflammation by increasing vascular permeability and the contraction of bronchial smooth muscle. Recently, we and other groups suggested that the LTB4–BLT1 axis and the cysteinyl LTs–CysLT1/2 axis are involved in chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, atherosclerosis, arthritis, obesity, cancer and age-related macular degeneration using animal models for disease and gene knockout mice. This review describes the classical and novel functions of LTs and their receptors in several inflammatory diseases and discusses the potential clinical applications of antagonists for LT receptors and inhibitors of LT biosynthesis.
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11

Drost, Adriana, Mirjam Funk, Karoline Norz, Anne Zipfel, Lothar Kanz, and Robert Mohle. "Cysteinyl Leukotrienes Signal Via Overexpressed CysLT1, but Not CysLT2 Receptor In Chronic Lymphocytic Leukemia." Blood 116, no. 21 (November 19, 2010): 3612. http://dx.doi.org/10.1182/blood.v116.21.3612.3612.

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Abstract Abstract 3612 The G Protein-coupled receptors (GPCRs) CysLT1 and CysLT2 are both expressed in peripheral blood mononuclear cells (PBMNC). Their ligands are inflammatory mediators of the cysteinyl leukotriene (cysLT) family and contribute, together with ligands of other GPCRs such as chemokines, to migration and proliferation of a variety of cell types. In the present study, we demonstrate by real-time RT-PCR that CysLT1 mRNA is overexpressed in B-CLL cells compared to both normal PBMNC and normal CD19+ B cells, whereas only low levels of CysLT2 mRNA are present. GPCR-typical cellular responses such as intracellular calcium fluxes and actin polymerization, which were induced by the cysLT LTD4 in CLL cells in a dose-dependent manner, were suppressed by the CysLT1 antagonist MK571, the prototype of the lukast family of drugs used in asthma treatment (e.g., montelukast). However, MK571 and other lukasts also block the leukotriene transporter MRP. The fact that the CysLT1 antagonist LY171883, which has no effect on MRP, also abrogated the responses of CLL cells indicates that the effects of cysLTs are mediated solely by CysLT1. Moreover, also chemotaxis was induced by the cysLT LTD4 in B-CLL cells (optimum at low nanomolar concentrations) and could be blocked by MK571. We further observed inhibiting effects of MK571 on cysLT-induced Erk/MAP kinase phosphorylation in B-CLL cells, which suggests an involvement of CysLT1 in cell proliferation. Indeed, MK571 significantly induced apoptosis of CLL cells in vitro and reduced survival of cultured B-CLL cells. However, the concentrations for a significant reduction of cell viability were higher (1-10 μM) than the concentration required for efficient CysLT1 receptor inhibition (0.1 μM). Thus, the influence of MK571 on B-CLL cell survival may mainly be due to direct effects on apoptosis occuring at the higher dose level and/or blocking of the leukotriene transporter MRP. Accordingly, LY171883 and the combined CysLT1/2 antagonist Bay-u9773 did not induce CLL apoptosis. Our results suggest that CysLT1 is overexpressed in B-CLL cells and involved in cell trafficking, similar to the chemokine receptor CXCR4. Considering the redundancy among GPCRs and the limited effect of MK571 on cell survival, CysLT1 for its own represents a less attractive therapeutic target using the currently available CysLT1 antagonists of the lukast family. However, combined inhibition of several GPCRs highly expressed in CLL cells including cysLT1 and CXCR4 may constitute a promising therapeutic approach and should be further evaluated. Disclosures: No relevant conflicts of interest to declare.
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12

Yoshioka, Masakata, Hironori Sagara, Fumiyuki Takahashi, Norihiro Harada, Kazuto Nishio, Akio Mori, Hiroko Ushio, et al. "Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation." American Journal of Physiology-Lung Cellular and Molecular Physiology 296, no. 1 (January 2009): L30—L36. http://dx.doi.org/10.1152/ajplung.00026.2008.

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Multidrug resistance-associated protein 1 (MRP1) is a cysteinyl leukotriene (CysLT) export pump expressed on mast cells. CysLTs are crucial mediators in allergic airway disease. However, biological significance of MRP1 in allergic airway inflammation has not yet been elucidated. In this study, we sensitized wild-type control mice ( mrp1+/+) and MRP1-deficient mice ( mrp1−/−) to ovalbumin (OVA) and challenged them with OVA by aerosol. Airway inflammation and goblet cell hyperplasia after OVA exposure were reduced in mrp1−/− mice compared with mrp1+/+ mice. Furthermore, CysLT levels in bronchoalveolar lavage fluid (BALF) from OVA-exposed mrp1−/− mice were significantly lower than those from OVA-exposed mrp1+/+ mice. Levels of OVA-specific IgE, IL-4, and IL-13 in BALF were also decreased in OVA-exposed mrp1−/− mice. IgE-mediated release of CysLTs from murine bone marrow-derived mast cells was markedly impaired by MRP1 deficiency. Our results indicate that MRP1 plays an important role in the development of allergic airway inflammation through regulation of IgE-mediated CysLT export from mast cells.
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13

Shrestha Palikhe, Nami, Seung-Hyun Kim, Hyun Jung Jin, Eui-Kyung Hwang, Young Hee Nam, and Hae-Sim Park. "Genetic Mechanisms in Aspirin-Exacerbated Respiratory Disease." Journal of Allergy 2012 (August 7, 2012): 1–6. http://dx.doi.org/10.1155/2012/794890.

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Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the exposure to aspirin or other nonsteroidal anti-inflammatory drugs. The key pathogenic mechanisms associated with AERD are the overproduction of cysteinyl leukotrienes (CysLTs) and increased CysLTR1 expression in the airway mucosa and decreased lipoxin and PGE2 synthesis. Genetic studies have suggested a role for variability of genes in disease susceptibility and the response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10, ACE, IL13, KIF3A, SLC22A2, CEP68, PTGER, and CRTH2 and a four-locus SNP set composed of B2ADR, CCR3, CysLTR1, and FCER1B. Future areas of investigation need to focus on comprehensive approaches to identifying biomarkers for early diagnosis.
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14

Ribeiro, Laura R. R., Flávio V. Loures, Eliseu F. de Araújo, Cláudia Feriotti, Tânia A. Costa, Carlos Henrique Serezani, Sonia Jancar, and Vera L. G. Calich. "Lipoxin Inhibits Fungal Uptake by Macrophages and Reduces the Severity of Acute Pulmonary Infection Caused byParacoccidioides brasiliensis." Mediators of Inflammation 2015 (2015): 1–17. http://dx.doi.org/10.1155/2015/852574.

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Cysteinyl leukotrienes (CysLTs) and lipoxins (LXs) are lipid mediators that control inflammation, with the former inducing and the latter inhibiting this process. Because the role played by these mediators in paracoccidioidomycosis was not investigated, we aimed to characterize the role of CysLT in the pulmonary infection developed by resistant (A/J) and susceptible (B10.A) mice. 48 h after infection, elevated levels of pulmonary LTC4and LXA4were produced by both mouse strains, but higher levels were found in the lungs of susceptible mice. Blocking the CysLTs receptor by MTL reduced fungal loads in B10.A, but not in A/J mice. In susceptible mice, MLT treatment led to reduced influx of PMN leukocytes, increased recruitment of monocytes, predominant synthesis of anti-inflammatory cytokines, and augmented expression of 5- and 15-lipoxygenase mRNA, suggesting a prevalent LXA4activity. In agreement, MTL-treated macrophages showed reduced fungal burdens associated with decreased ingestion of fungal cells. Furthermore, the addition of exogenous LX reduced, and the specific blockade of the LX receptor increased the fungal loads of B10.A macrophages. This study showed for the first time that inhibition of CysLTs signaling results in less severe pulmonary paracoccidioidomycosis that occurs in parallel with elevated LX activity and reduced infection of macrophages.
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Gelosa, Paolo, Francesca Colazzo, Elena Tremoli, Luigi Sironi, and Laura Castiglioni. "Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases." Mediators of Inflammation 2017 (2017): 1–15. http://dx.doi.org/10.1155/2017/3454212.

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Cysteinyl leukotrienes (CysLTs) are potent lipid mediators widely known for their actions in asthma and in allergic rhinitis. Accumulating data highlights their involvement in a broader range of inflammation-associated diseases such as cancer, atopic dermatitis, rheumatoid arthritis, and cardiovascular diseases. The reported elevated levels of CysLTs in acute and chronic brain lesions, the association between the genetic polymorphisms in the LTs biosynthesis pathways and the risk of cerebral pathological events, and the evidence from animal models link also CysLTs and brain diseases. This review will give an overview of how far research has gone into the evaluation of the role of CysLTs in the most prevalent neurodegenerative disorders (ischemia, Alzheimer’s and Parkinson’s diseases, multiple sclerosis/experimental autoimmune encephalomyelitis, and epilepsy) in order to understand the underlying mechanism by which they might be central in the disease progression.
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Laroche, Dominique, Pierre Léturgie, Delphine Mariotte, Yann Ollivier, Jean-Luc Hanouz, Brigitte Le Mauff, and Jean-Jacques Parienti. "In Vivo Cysteinyl Leukotriene Release in Allergic and Nonallergic Immediate Hypersensitivity Reactions during Anesthesia." Anesthesiology 126, no. 5 (May 1, 2017): 834–41. http://dx.doi.org/10.1097/aln.0000000000001600.

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Abstract Background Immediate hypersensitivity reactions occurring during anesthesia are classified as allergic when skin tests and mast cell tryptase are positive and as nonallergic when negative results are obtained. Cysteinyl leukotrienes (cysLTs) are potent mediators synthesized by mast cell and eosinophil that induce bronchial constriction. They could play a role in hypersensitivity reactions. Methods cysLT C4, D4, and E4 concentrations were measured by a competition immunoassay in serial plasma samples obtained prospectively from 21 anesthetized controls and retrospectively from 34 patients who reacted at induction of anesthesia (24 with allergic and 10 with nonallergic reactions). Results In controls, the median (interquartile range) cysLT concentration was 0.83 (0.69 to 1.02) μg/l before anesthesia and was unchanged 30 min, 6 h, and 24 h afterward. In the patients with allergic reactions, the values were highly increased 30 to 60 min after the reaction (17.9 [7.8 to 36.0] μg/l), while the patients with nonallergic reactions had less increased values (7.3 [3.0 to 11.5] μg/l). The difference between the three groups was significant (P &lt; 0.0001). Increased values persisted during the 24 h of observation. Concentrations were significantly higher in patients with bronchospasm (P = 0.016). Conclusions cysLTs appear to be an important mediator of allergic and nonallergic immediate hypersensitivity reactions. These findings might open a new field for management of patients with hypersensitivity reactions, especially nonallergic ones.
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Haberal, Ilknur, and Jacquelynne P. Corey. "The Role of Leukotrienes in Nasal Allergy." Otolaryngology–Head and Neck Surgery 129, no. 3 (September 2003): 274–79. http://dx.doi.org/10.1016/s0194-5998(03)00601-6.

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OBJECTIVE: This review focuses on the role of cysteinyl leukotrienes (cysLTs) in nasal allergy. The purpose was to provide knowledge of the role of cysLTs in the pathophysiology of nasal allergy and the role of antileukotrienes in the treatment of nasal allergies. MATERIALS AND METHODS: We conducted a literature review. RESULTS: The proinflammatory effects of cysLTs have been well described in asthma. Antileukotrienes have proved to be an effective anti-inflammatory treatment for asthma patients. Similar to pathogenesis of asthma, cysLTs exert potent inflammatory effects in the upper airways and play a role in the pathogenesis of allergic rhinitis and other nasal allergies. CONCLUSION: Antileukotriene treatment appears to be beneficial in nasal allergies. Allergic rhinitis is a complex, IgE-mediated inflammatory disease of the upper airways. It is the most common allergic disease, occurring in 10% to 30% of adults and up to 30% of children. It may be perennial or seasonal. Sneezing, itching, watery rhinorrhea, and nasal obstruction are classic symptoms. It may impair cognition, school/work performance and productivity, behavior, mood, and quality of life. On physical examination, clear secretions, nasal congestion, pink-bluish nasal mucosa, the allergic salute, and allergic shiners may be detected. Allergic rhinitis is a common comorbid condition with asthma, sinusitis, otitis media, nasal polyposis, and respiratory infections.
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James, A. J., and A. P. Sampson. "A Tale of Two CysLTs." Clinical & Experimental Allergy 31, no. 11 (November 2001): 1660–64. http://dx.doi.org/10.1046/j.1365-2222.2001.01259.x.

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19

Field, Joshua J., Adetola Kassim, Amanda Brandow, Stephen H. Embury, Neil Matsui, Karina Wilkerson, Valencia Bryant, Liyun Zhang, Pippa Simpson, and Michael R. DeBaun. "Phase 2 trial of montelukast for prevention of pain in sickle cell disease." Blood Advances 4, no. 6 (March 24, 2020): 1159–65. http://dx.doi.org/10.1182/bloodadvances.2019001165.

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Abstract Cysteinyl leukotrienes (CysLTs) are lipid mediators of inflammation. In patients with sickle cell disease (SCD), levels of CysLTs are increased compared with controls and associated with a higher rate of hospitalization for pain. We tested the hypothesis that administration of the CysLT receptor antagonist montelukast would improve SCD-related comorbidities, including pain, in adolescents and adults with SCD. In a phase 2 randomized trial, we administered montelukast or placebo for 8 weeks. The primary outcome measure was a &gt;30% reduction in soluble vascular cell adhesion molecule 1 (sVCAM), a marker of vascular injury. Secondary outcome measures were reduction in daily pain, improvement in pulmonary function, and improvement in microvascular blood flow, as measured by laser Doppler velocimetry. Forty-two participants with SCD were randomized to receive montelukast or placebo for 8 weeks. We found no difference between the montelukast and placebo groups with regard to the levels of sVCAM, reported pain, pulmonary function, or microvascular blood flow. Although montelukast is an effective treatment for asthma, we did not find benefit for SCD-related outcomes. This clinical trial was registered at www.clinicaltrials.gov as #NCT01960413.
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20

Ballerini, P., R. Ciccarellf, F. Caciagli, M. P. Rathbone, E. S. Werstiuk, U. Traversa, S. Buccella, et al. "P2X7 Receptor Activation in Rat Brain Cultured Astrocytes Increases the Biosynthetic Release of Cysteinyl Leukotrienes." International Journal of Immunopathology and Pharmacology 18, no. 3 (July 2005): 417–30. http://dx.doi.org/10.1177/039463200501800303.

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Astrocytes have been recognized as important elements in controlling inflammatory as well as immune processes in the central nervous system (CNS). Recently, glial cells have been shown to produce cysteinyl leukotrienes (CysLTs) which are known lipid mediators of inflammation and whose extracellular concentrations rise under different pathological conditions in the brain. In the same conditions also extracellular concentrations of ATP dramatically increase reaching levels able to activate P2X7 ionotropic receptors for which an emerging role in neuroinflammation and neurodegeneration has been claimed. RT-PCR analysis showed that primary cultures of rat brain astrocytes express P2X7 receptors. Application of the selective P2X7 agonist benzoyl-benzolyATP (BzATP) markedly increased [Ca2+]i which was mediated by a calcium influx from the extracellular milieu. The P2X7 antagonist, oATP, suppressed the BzATP-induced calcium increase. Consistent with the evidence that increased calcium levels activate the leukotriene biosynthetic pathway, challenge of astrocytes with either the calcium ionophore A23187 or BzATP significantly increased CysLT production and the cell pre-treatment with EGTA abolished these effects. Again the P2X7 antagonist prevented the BzATP-mediated CysLT efflux, whereas the astrocyte pre-treatment with MK-571, a CysLT, receptor antagonist, was ineffective. The astrocyte pre-treatment with a cocktail of inhibitors of ATP binding cassette (ABC) proteins reduced the BzATP-mediated CysLT production confirming that ABC transporters are involved in the release of CysLTs. The astrocyte P2X7-evoked rise of CysLT efflux was abolished in the presence of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP) whose expression, along with that of 5′-lipoxygenase (5-LO) was reported by Northern Blot analysis. The stimulation of P2X7 induced an up-regulation of FLAP mRNA that was reduced by the antagonist oATP. These data suggest that in rat brain cultured astrocytes P2X7 ATP receptors may participate in the control of CysLT release thus further supporting a role for extracellular ATP as an integral component of the inflammatory brain response.
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Penno, Carlos A., Nathalie Wack, Claire Laguerre, Franziska Hasler, Shin Numao, and Till A. Röhn. "Comment on “An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness”." Science Translational Medicine 11, no. 497 (June 19, 2019): eaav4538. http://dx.doi.org/10.1126/scitranslmed.aav4538.

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22

Early, S., K. Hise, L. Borish, and J. W. Steinke. "Cysteinyl Leukotrienes (CysLTs) Stimulate Eosinophil Degranulation in a CysLT1 Receptor Antagonist Independent Fashion." Journal of Allergy and Clinical Immunology 117, no. 2 (February 2006): S206. http://dx.doi.org/10.1016/j.jaci.2005.12.812.

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23

Duah, Ernest, Lakshminarayan Reddy Teegala, Vinay Kondeti, Ravi K. Adapala, Venkateshwar G. Keshamouni, Yoshihide Kanaoka, K. Frank Austen, Charles K. Thodeti, and Sailaja Paruchuri. "Cysteinyl leukotriene 2 receptor promotes endothelial permeability, tumor angiogenesis, and metastasis." Proceedings of the National Academy of Sciences 116, no. 1 (December 17, 2018): 199–204. http://dx.doi.org/10.1073/pnas.1817325115.

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Cysteinyl leukotrienes (cys-LTs) are proinflammatory mediators that enhance vascular permeability through distinct receptors (CysLTRs). We found that CysLT2R regulates angiogenesis in isolated mouse endothelial cells (ECs) and in Matrigel implants in WT mice and enhances EC contraction and permeability via the Rho-dependent myosin light chain 2 and vascular endothelial (VE)-cadherin axis. Since solid tumors utilize aberrant angiogenesis for their growth and metastasis and their vessels exhibit vascular hyperpermeability, we hypothesized that CysLT2R, via its actions on the endothelium, might regulate tumor growth. Both tumor growth and metastases of adoptively transferred syngeneic Lewis lung carcinoma (LLC) cells are significantly reduced in CysLT2R-null mice (Cysltr2−/−) compared with WT and CysLT1R-null mice (Cysltr1−/−). In WT recipients of LLC cells, CysLT2R expression is significantly increased in the tumor vasculature, compared with CysLT1R. Further, the tumor vasculature in Cysltr2−/− recipients exhibited significantly improved integrity, as revealed by increased pericyte coverage and decreased leakage of i.v.-administered Texas Red-conjugated dextran. Administration of a selective CysLT2R antagonist significantly reduced LLC tumor volume, vessel density, dextran leakage, and metastases in WT mice, highlighting CysLT2R as a VEGF-independent regulator of the vasculature promoting risk of metastasis. Thus, both genetic and pharmacological findings establish CysLT2R as a gateway for angiogenesis and EC dysregulation in vitro and ex vivo and in an in vivo model with a mouse tumor. Our data suggest CysLT2R as a possible target for intervention.
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Fumagalli, Marta, Simona Daniele, Davide Lecca, Philip R. Lee, Chiara Parravicini, R. Douglas Fields, Patrizia Rosa, et al. "Phenotypic Changes, Signaling Pathway, and Functional Correlates of GPR17-expressing Neural Precursor Cells during Oligodendrocyte Differentiation." Journal of Biological Chemistry 286, no. 12 (January 4, 2011): 10593–604. http://dx.doi.org/10.1074/jbc.m110.162867.

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The developing and mature central nervous system contains neural precursor cells expressing the proteoglycan NG2. Some of these cells continuously differentiate to myelin-forming oligodendrocytes; knowledge of the destiny of NG2+ precursors would benefit from the characterization of new key functional players. In this respect, the G protein-coupled membrane receptor GPR17 has recently emerged as a new timer of oligodendrogliogenesis. Here, we used purified oligodendrocyte precursor cells (OPCs) to fully define the immunophenotype of the GPR17-expressing cells during OPC differentiation, unveil its native signaling pathway, and assess the functional consequences of GPR17 activation by its putative endogenous ligands, uracil nucleotides and cysteinyl leukotrienes (cysLTs). GPR17 presence was restricted to very early differentiation stages and completely segregated from that of mature myelin. Specifically, GPR17 decorated two subsets of slowly proliferating NG2+ OPCs: (i) morphologically immature cells expressing other early proteins like Olig2 and PDGF receptor-α, and (ii) ramified preoligodendrocytes already expressing more mature factors, like O4 and O1. Thus, GPR17 is a new marker of these transition stages. In OPCs, GPR17 activation by either uracil nucleotides or cysLTs resulted in potent inhibition of intracellular cAMP formation. This effect was counteracted by GPR17 antagonists and receptor silencing with siRNAs. Finally, uracil nucleotides promoted and GPR17 inhibition, by either antagonists or siRNAs, impaired the normal program of OPC differentiation. These data have implications for the in vivo behavior of NG2+ OPCs and point to uracil nucleotides and cysLTs as main extrinsic local regulators of these cells under physiological conditions and during myelin repair.
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Yadav, U. C. S., and S. K. Srivastava. "Cysteinyl Leukotrienes (CysLTs): Role in Obesity-Induced Asthma." Current Molecular Medicine 15, no. 7 (September 3, 2015): 598–605. http://dx.doi.org/10.2174/1566524015666150831130954.

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26

Laidlaw, Tanya M., Molly S. Kidder, Neil Bhattacharyya, Wei Xing, Shiliang Shen, Ginger L. Milne, Mariana C. Castells, Heng Chhay, and Joshua A. Boyce. "Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes." Blood 119, no. 16 (April 19, 2012): 3790–98. http://dx.doi.org/10.1182/blood-2011-10-384826.

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Abstract Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocyte-derived precursor leukotriene (LT)A4 to LTC4, the parent cysLT, through the terminal enzyme LTC4 synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirin-tolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC4 synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC4 generation by activated granulocytes from subjects with AERD compared with aspirin-tolerant controls. Urinary LTE4 levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in platelet-leukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD.
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27

Bonvini, Sara J., Mark A. Birrell, Eric Dubuis, John J. Adcock, Michael A. Wortley, Pauline Flajolet, Peter Bradding, and Maria G. Belvisi. "Novel airway smooth muscle–mast cell interactions and a role for the TRPV4-ATP axis in non-atopic asthma." European Respiratory Journal 56, no. 1 (April 16, 2020): 1901458. http://dx.doi.org/10.1183/13993003.01458-2019.

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Mast cell–airway smooth muscle (ASM) interactions play a major role in the immunoglobulin (Ig)E- dependent bronchoconstriction seen in asthma but less is known about IgE-independent mechanisms of mast cell activation. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) activation causes contraction of human ASM via the release of cysteinyl leukotrienes (cysLTs) but the mechanism is unknown. The objective of the present study was to investigate a role for IgE-independent, mast cell–ASM interaction in TRPV4-induced bronchospasm.Bronchoconstriction was measured in anaesthetised guinea pigs and contraction of human and guinea-pig airway tissue assessed using isometric tension measurements. Increases in intracellular [Ca2+] were imaged using the Ca2+-sensitive dye FURA2, and time-lapse ptychography was utilised as a surrogate for contraction of ASM cells.The TRPV4 agonist GSK1016790A caused contraction in vivo in the guinea pig, and in human and guinea-pig tracheal tissue, which was inhibited by the TRPV4 antagonist GSK2193874. GSK1016790A increased [Ca2+]i and released ATP in human ASM cells without causing contraction. TRPV4 and ATP evoked contraction in isolated tracheal tissue but co-culture experiments indicated a requirement for human lung mast cells. Expression profiling and pharmacological studies demonstrated that mast cell activation was dependent upon ATP activating the P2X4 receptor. Trypsin was shown to evoke contraction of tracheal tissue via activation of PAR-2-TRPV4-ATP-cysLT axis indicating the potential disease relevance of this signalling pathway.TRPV4 activation increases [Ca2+]i and releases ATP from ASM cells triggering P2X4-dependent release of cysLTs from mast cells resulting in ASM contraction. This study delineates a novel mast cell–ASM interaction and TRPV4 as a driver of IgE-independent mast cell-dependent bronchospasm.
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28

Yang, Guochang, Angela Haczku, Hang Chen, Viviane Martin, Helen Galczenski, Yaniv Tomer, Christopher R. Van Beisen, Jilly F. Evans, Reynold A. Panettieri, and Colin D. Funk. "Transgenic smooth muscle expression of the human CysLT1 receptor induces enhanced responsiveness of murine airways to leukotriene D4." American Journal of Physiology-Lung Cellular and Molecular Physiology 286, no. 5 (May 2004): L992—L1001. http://dx.doi.org/10.1152/ajplung.00367.2003.

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Cysteinyl leukotrienes (CysLTs) exert potent proinflammatory actions and contribute to many of the symptoms of asthma. Using a model of allergic sensitization and airway challenge with Aspergillus fumigatus ( Af), we have found that Th2-type inflammation and airway hyperresponsiveness (AHR) to methacholine (MCh) were associated with increased LTD4 responsiveness in mice. To explore the importance of increased CysLT signaling in airway smooth muscle function, we generated transgenic mice that overexpress the human CysLT1 receptor (hCysLT1R) via the α-actin promoter. These receptors were expressed abundantly and induced intracellular calcium mobilization in airway smooth muscle cells from transgenic mice. Force generation in tracheal ring preparations ex vivo and airway reactivity in vivo in response to LTD4 were greatly amplified in hCysLT1R-overexpressing mice, indicating that the enhanced signaling induces coordinated functional changes of the intact airway smooth muscle. The increase of AHR imposed by overexpression of the hCysLT1R was greater in transgenic BALB/c mice than in transgenic B6 × SJL mice. In addition, sensitization- and challenge-induced increases in airway responsiveness were significantly greater in transgenic mice than that of nontransgenic mice compared with their respective nonsensitized controls. The amplified AHR in sensitized transgenic mice was not due to an enhanced airway inflammation and was not associated with similar enhancement in MCh responsiveness. These results indicate that a selective hCysLT1R-induced contractile mechanism synergizes with allergic AHR. We speculate that hCysLT1R signaling contributes to a hypercontractile state of the airway smooth muscle.
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Wedde-Beer, Katrin, Chengping Hu, Maria M. Rodriguez, and Giovanni Piedimonte. "Leukotrienes mediate neurogenic inflammation in lungs of young rats infected with respiratory syncytial virus." American Journal of Physiology-Lung Cellular and Molecular Physiology 282, no. 5 (May 1, 2002): L1143—L1150. http://dx.doi.org/10.1152/ajplung.00323.2001.

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Respiratory syncytial virus (RSV) infection potentiates neurogenic inflammation in rat airways. Because some vascular effects of sensory nerves are mediated by cysteinyl leukotrienes (cysLTs), we studied whether the receptor antagonist montelukast inhibits neurogenic plasma extravasation in RSV-infected rats. Pathogen-free rats were inoculated at 2 wk (weanlings) or 12 wk (adults) of age with RSV or virus-free medium and treated with montelukast or its vehicle starting 1 day before inoculation. Five days postinoculation, we measured the extravasation of Evans blue-labeled albumin in the respiratory tract after stimulation of sensory nerves with capsaicin. Montelukast had no effect in the extrapulmonary airways but abolished albumin extravasation in the intrapulmonary airways of RSV-infected rats, with a larger effect in weanlings than in adults. Increased concentrations of 5-lipoxygenase-encoding mRNA and cysLTs, as well as numerous mast cells, were detected in the lung tissues of RSV-infected weanling rats. These observations suggest that the release of neuropeptides from capsaicin-sensitive sensory nerves and nonneuronal cells in the lungs of RSV-infected young rats increases vascular permeability by promoting the release of leukotrienes from mast cells.
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Musiyenko, Alla, Lucia Correa, Nicholas Stock, John H. Hutchinson, Daniel S. Lorrain, Gretchen Bain, Jilly F. Evans, and Sailen Barik. "A Novel 5-Lipoxygenase-Activating Protein Inhibitor, AM679, Reduces Inflammation in the Respiratory Syncytial Virus-Infected Mouse Eye." Clinical and Vaccine Immunology 16, no. 11 (September 16, 2009): 1654–59. http://dx.doi.org/10.1128/cvi.00220-09.

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ABSTRACT Respiratory syncytial virus (RSV) is an important cause of viral respiratory disease in children, and RSV bronchiolitis has been associated with the development of asthma in childhood. RSV spreads from the eye and nose to the human respiratory tract. Correlative studies of humans and direct infection studies of BALB/c mice have established the eye as a significant pathway of entry of RSV to the lung. At the same time, RSV infection of the eye produces symptoms resembling allergic conjunctivitis. Cysteinyl leukotrienes (CysLTs) are known promoters of allergy and inflammation, and the first step in their biogenesis from arachidonic acid is catalyzed by 5-lipoxygenase (5-LO) in concert with the 5-LO-activating protein (FLAP). We have recently developed a novel compound, AM679, which is a topically applied and potent inhibitor of FLAP. Here we show with the BALB/c mouse eye RSV infection model that AM679 markedly reduced the RSV-driven ocular pathology as well as the synthesis of CysLTs in the eye. In addition, AM679 decreased the production of the Th2 cell cytokine interleukin-4 but did not increase the viral load in the eye or the lung. These results suggest that FLAP inhibitors may be therapeutic for RSV-driven eye disease and possibly other inflammatory eye indications.
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31

Ualiyeva, Saltanat, Nils Hallen, Yoshihide Kanaoka, Carola Ledderose, Ichiro Matsumoto, Wolfgang G. Junger, Nora A. Barrett, and Lora G. Bankova. "Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2." Science Immunology 5, no. 43 (January 17, 2020): eaax7224. http://dx.doi.org/10.1126/sciimmunol.aax7224.

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Chemosensory epithelial cells (EpCs) are specialized cells that promote innate type 2 immunity and protective neurally mediated reflexes in the airway. Their effector programs and modes of activation are not fully understood. Here, we define the transcriptional signature of two choline acetyltransferase–expressing nasal EpC populations. They are found in the respiratory and olfactory mucosa and express key chemosensory cell genes including the transcription factor Pou2f3, the cation channel Trpm5, and the cytokine Il25. Moreover, these cells share a core transcriptional signature with chemosensory cells from intestine, trachea and thymus, and cluster with tracheal brush cells (BrCs) independently from other respiratory EpCs, indicating that they are part of the brush/tuft cell family. Both nasal BrC subsets express high levels of transcripts encoding cysteinyl leukotriene (CysLT) biosynthetic enzymes. In response to ionophore, unfractionated nasal BrCs generate CysLTs at levels exceeding that of the adjacent hematopoietic cells isolated from naïve mucosa. Among activating receptors, BrCs express the purinergic receptor P2Y2. Accordingly, the epithelial stress signal ATP and aeroallergens that elicit ATP release trigger BrC CysLT generation, which is mediated by the P2Y2 receptor. ATP- and aeroallergen-elicited CysLT generation in the nasal lavage is reduced in mice lacking Pou2f3, a requisite transcription factor for BrC development. Last, aeroallergen-induced airway eosinophilia is reduced in BrC-deficient mice. These results identify a previously undescribed BrC sensor and effector pathway leading to generation of lipid mediators in response to luminal signals. Further, they suggest that BrC sensing of local damage may provide an important sentinel immune function.
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Slater, Kayleigh, Aisling B. Heeran, Sandra Garcia-Mulero, Helen Kalirai, Rebeca Sanz-Pamplona, Arman Rahman, Nebras Al-Attar, et al. "High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells." Cancers 12, no. 10 (October 13, 2020): 2950. http://dx.doi.org/10.3390/cancers12102950.

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Metastatic uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic UM, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified that high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012; HR 2.76; 95% CI 1.21–6.3) and overall survival (p = 0.011; HR 1.46; 95% CI 0.67–3.17). High CysLT1 expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT1 were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT2. Quininib, a selective CysLT1 antagonist, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05) but significantly upregulated IL-10, IL-1β, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM.
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33

Poulin, S., C. Thompson, C. M. Dubois, J. Stankova, and M. Rola-Pleszczynski. "Cys-Leukotrienes (cysLTs) Stimulate the Expression of Vascular Endothelial Growth Factor (VEGF)." Journal of Allergy and Clinical Immunology 121, no. 3 (March 2008): 791–92. http://dx.doi.org/10.1016/j.jaci.2008.01.040.

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34

Murphy, Ryan C., Ying Lai, James D. Nolin, Robier A. Aguillon Prada, Arindam Chakrabarti, Michael V. Novotny, Michael C. Seeds, et al. "Exercise-induced alterations in phospholipid hydrolysis, airway surfactant, and eicosanoids and their role in airway hyperresponsiveness in asthma." American Journal of Physiology-Lung Cellular and Molecular Physiology 320, no. 5 (May 1, 2021): L705—L714. http://dx.doi.org/10.1152/ajplung.00546.2020.

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The mechanisms responsible for driving endogenous airway hyperresponsiveness (AHR) in the form of exercise-induced bronchoconstriction (EIB) are not fully understood. We examined alterations in airway phospholipid hydrolysis, surfactant degradation, and lipid mediator release in relation to AHR severity and changes induced by exercise challenge. Paired induced sputum ( n = 18) and bronchoalveolar lavage (BAL) fluid ( n = 11) were obtained before and after exercise challenge in asthmatic subjects. Samples were analyzed for phospholipid structure, surfactant function, and levels of eicosanoids and secreted phospholipase A2 group 10 (sPLA2-X). A primary epithelial cell culture model was used to model effects of osmotic stress on sPLA2-X. Exercise challenge resulted in increased surfactant degradation, phospholipase activity, and eicosanoid production in sputum samples of all patients. Subjects with EIB had higher levels of surfactant degradation and phospholipase activity in BAL fluid. Higher basal sputum levels of cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) were associated with direct AHR, and both the postexercise and absolute change in CysLTs and PGD2 levels were associated with EIB severity. Surfactant function either was abnormal at baseline or became abnormal after exercise challenge. Baseline levels of sPLA2-X in sputum and the absolute change in amount of sPLA2-X with exercise were positively correlated with EIB severity. Osmotic stress ex vivo resulted in movement of water and release of sPLA2-X to the apical surface. In summary, exercise challenge promotes changes in phospholipid structure and eicosanoid release in asthma, providing two mechanisms that promote bronchoconstriction, particularly in individuals with EIB who have higher basal levels of phospholipid turnover.
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35

Sadybekov, Arman A., Rebecca L. Brouillette, Egor Marin, Anastasiia V. Sadybekov, Aleksandra Luginina, Anastasiia Gusach, Alexey Mishin, et al. "Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR." Biomolecules 10, no. 12 (December 3, 2020): 1634. http://dx.doi.org/10.3390/biom10121634.

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Cysteinyl leukotriene G protein-coupled receptors, CysLT1R and CysLT2R, regulate bronchoconstrictive and pro-inflammatory effects and play a key role in allergic disorders, cardiovascular diseases, and cancer. CysLT1R antagonists have been widely used to treat asthma disorders, while CysLT2R is a potential target against uveal melanoma. However, very few selective antagonist chemotypes for CysLT receptors are available, and the design of such ligands has proved to be challenging. To overcome this obstacle, we took advantage of recently solved crystal structures of CysLT receptors and an ultra-large Enamine REAL library, representing a chemical space of 680 M readily available compounds. Virtual ligand screening employed 4D docking models comprising crystal structures of CysLT1R and CysLT2R and their corresponding ligand-optimized models. Functional assessment of the candidate hits yielded discovery of five novel antagonist chemotypes with sub-micromolar potencies and the best Ki = 220 nM at CysLT1R. One of the hits showed inverse agonism at the L129Q constitutively active mutant of CysLT2R, with potential utility against uveal melanoma.
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36

Sloane, David E., Nicodemus Tedla, Muyiwa Awoniyi, Donald W. MacGlashan, Luis Borges, K. Frank Austen, and Jonathan P. Arm. "Leukocyte immunoglobulin-like receptors: novel innate receptors for human basophil activation and inhibition." Blood 104, no. 9 (November 1, 2004): 2832–39. http://dx.doi.org/10.1182/blood-2004-01-0268.

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Abstract Basophils, recruited from the blood to tissues, have been implicated by their presence in diverse allergic disorders including bronchial asthma, allergic rhinitis, and cutaneous contact hypersensitivity. We hypothesized that like other leukocytes involved in inflammatory responses, basophils would express members of the leukocyte immunoglobulin-like receptor (LIR) family of immuno-regulatory molecules on their cell surface. We identified LIR7, an activating member coupled to the common Fc receptor gamma chain, and LIR3, an inhibitory member containing cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, on these cells from human peripheral blood. Cross-linking of LIR7 resulted in the concentration-dependent net release of histamine (29.8 ± 10.8%) and cysteinyl leukotrienes (cysLTs) (31.4 ± 8.7 ng/106 basophils) that were maximal at 30 minutes, and of interleukin-4 (IL-4) (410.2 ± 61.6 pg/106 basophils) that was maximal at 4 hours and comparable with the response initiated by cross-linking of the high-affinity receptor for immunoglobulin E (FcϵRI). Coligation of LIR3 to LIR7 or to FcϵRI by means of a second monoclonal antibody significantly inhibited net histamine release, cysLT production, and IL-4 generation. That LIR3 is profoundly counter-regulatory for both adaptive and innate receptors suggests a broad role in containment of the inflammatory response.
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Nayak, Bipin Kumar, Arun Kumar, and Preeti Kothiyal. "PHARMACOLOGICAL EVALUATION OF ZAFIRLUKAST IN EXPERIMENTALLY INDUCED GLOBAL CEREBRAL ISCHEMIA/REPERFUSION INJURY IN MICE." International Journal of Pharmacy and Pharmaceutical Sciences 10, no. 2 (February 1, 2018): 30. http://dx.doi.org/10.22159/ijpps.2018v10i2.21633.

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Objective: Cysteinyl leukotrienes (CysLTs) are potent mediators of inflammation that are associated with cerebral ischemia/reperfusion (I/R) injury. The CysLTs receptor antagonist may offer protection against ischemic injury. The present study was designed to investigate the role of zafirlukast in experimentally induced global cerebral ischemia/reperfusion (I/R) injury in mice.Methods: Global cerebral ischemia-reperfusion was induced by bilateral carotid artery occlusion for 17 min followed by 24 h reperfusion. Mice were randomly assigned to eight groups (n = 6 per group): control, sham-operated, I/R control, prednisolone treated group (5 mg/kg, p. o.) for 10 d, zafirlukast treated group (5, 10, 20 mg/kg, p. o.) for 10 d and combination group treated with zafirlukast (5 mg/kg, p. o.)+nifedipine (5 mg/kg, i. p.) for 10 d before ischemia/reperfusion. At the end of reperfusion (24 h), a blood sample was collected from retro-orbital route and mice’s brain was removed by cervical dislocation to measure serum lactate dehydrogenase (LDH), serum nitrite concentration, malondialdehyde (MDA), and cerebral infarct size.Results: Zafirlukast showed the dose-dependent neuroprotective activity by a significant decrease in lipid peroxidation, lactate dehydrogenase, serum nitrite level and cerebral infarct size. The high dose of zafirlukast (20 mg/kg, p. o.) and combination of zafirlukast (5 mg/kg, p. o.) with nifedipine (5 mg/kg, i. p.) showed the most potent neuroprotective effect against ischemic/reperfusion (I/R) group.Conclusion: This original study demonstrated the potency of zafirlukast in global cerebral ischemia/reperfusion injury. Also zafirlukast, in combination with nifedipine could represent a therapeutic approach to reduce inflammation associated with ischemia injury.
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Sjoberg, Jan, Frida Schain, Ylva Tryselius, Linda Backman, Maria Malec, Anna Porwit-MacDonald, Magnus Bjorkholm, and Hans-Erik Claesson. "Leukotrienes Stimulate the Release of Cytokines and Proliferation of Hodgkin Reed-Sternberg Cells." Blood 108, no. 11 (November 1, 2006): 2263. http://dx.doi.org/10.1182/blood.v108.11.2263.2263.

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Abstract Background: Classical Hodgkin Lymphoma (cHL) is characterized by a minority of malignant cells, the so-called Hodgkin- and Reed Sternberg (H-RS) cells, surrounded by inflammatory cells such as eosinophils, macrophages and mast cells. In contrast to other tumors, the malignant H-RS cells constitute only a few percent of the total cells in the affected tissue. Therefore, it is generally believed that various compounds released by H-RS cells and the interaction between H-RS cells and by- stander cells are of great importance in the pathophysiology of cHL disease. Aim: To characterize the expression and function of cysteinyl leukotriene receptors (CysLTR) in cHL. Methods and results: We have identified functional CysLT1R in a HL cell line as shown by increased intracellular calcium release upon leukotriene (LT) D4 stimulation (100–500 nM). This response was completely blocked after addition of zafirlukast, a specific CysLT1R antagonist. Immunohistochemical studies of paraffin embedded cHL tissue showed H-RS cells positive for CysLT1R in 12 of 16 cHL tumors. Microarray analysis of laser captured H-RS cells from 3 tumors not only confirmed the expression of CysLT1R transcripts, but also showed expression of the CysLT2R gene (P. Murray, personal communication). The possible role of the CysLT2R in H-RS cells will be discussed. The HL cell line was cultured in the presence of LTD4 (100 nM) to investigate the effects of CysLT signaling in H-RS cells. Real-time RT-PCR analysis showed up-regulation of TNF-α, interleukin (IL)-6, IL-8 and IL-13 mRNA after stimulation with LTD4. Furthermore, the effects of LTD4 on cytokine protein secretion by the HL cells were studied by flow cytometry. The results showed a markedly increased secretion of TNF-α, IL-6 and IL-8 upon LTD4 stimulation. In addition, LTD4 stimulated cell proliferation in a dose-dependent manner. Conclusion: Since H-RS cells are surrounded by CysLT producing cells (eosinophils, macrophages and mast cells), these results indicate that CysLT signaling could be of importance in the pathogenesis of cHL by contributing to proliferation of the tumor cell population and the disturbed cytokine features of this tumor. This study was supported by the Swedish Cancer Society.
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39

Jiang, Yongfeng, Laura A. Borrelli, Yoshihide Kanaoka, Brian J. Bacskai, and Joshua A. Boyce. "CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene–dependent mitogenic responses of mast cells." Blood 110, no. 9 (November 1, 2007): 3263–70. http://dx.doi.org/10.1182/blood-2007-07-100453.

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Abstract Cysteinyl leukotrienes (cys-LTs) induce inflammation through 2 G protein–coupled receptors (GPCRs), CysLT1 and CysLT2, which are coexpressed by most myeloid cells. Cys-LTs induce proliferation of mast cells (MCs), transactivate c-Kit, and phosphorylate extracellular signal-regulated kinase (ERK). Although MCs express CysLT2, their responses to cys-LTs are blocked by antagonists of CysLT1. We demonstrate that CysLT2 interacts with CysLT1, and that knockdown of CysLT2 increases CysLT1 surface expression and CysLT1-dependent proliferation of cord blood–derived human MCs (hMCs). Cys-LT–mediated responses were absent in MCs from mice lacking CysLT1 receptors, but enhanced by the absence of CysLT2 receptors. CysLT1 and CysLT2 receptors colocalized to the plasma membranes and nuclei of a human MC line, LAD2. Antibody-based fluorescent lifetime imaging microscopy confirmed complexes containing both receptors based on fluorescence energy transfer. Negative regulation of CysLT1-induced mitogenic signaling responses of MCs by CysLT2 demonstrates physiologically relevant functions for GPCR heterodimers on primary cells central to inflammation.
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40

Cheng, H. J., J. N. Yin, L. Liu, H. M. Qiao, and J. R. Lu. "The effect of TNF-α, IL-12 and CysLTs on the pathogenesis of MPP in children." Paediatric Respiratory Reviews 13 (June 2012): S61. http://dx.doi.org/10.1016/s1526-0542(12)70090-8.

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41

Saito, H., L. Crawford, E. Denburg, and J. A. Denburg. "The role of cysteinyl leukotrienes (CysLTS) in bone marrow responses in murine experimental allergic rhinitis: Blockade of eosinophil production and tissue eosinophilia by a CysLT1 receptor antagonist." Journal of Allergy and Clinical Immunology 111, no. 2 (February 2003): S266. http://dx.doi.org/10.1016/s0091-6749(03)80952-1.

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42

Witczak, Piotr, Ewa Brzezińska-Błaszczyk, and Justyna Agier. "The Response of Tissue Mast Cells to TLR3 Ligand Poly(I:C) Treatment." Journal of Immunology Research 2020 (February 24, 2020): 1–13. http://dx.doi.org/10.1155/2020/2140694.

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Mast cells (MCs) are found mainly at the anatomical sites exposed to the external environment; thus, they are localized close to blood vessels, lymphatic vessels, and a multitude of immune cells. Moreover, those cells can recognize invading pathogens through a range of surface molecules known as pathogen recognition receptors (PRRs), mainly Toll-like receptors (TLRs). MCs are extensively engaged in the control and clearance of bacterial infections, but much less is known about their contribution to antiviral host response as well as pathomechanisms of virus-induced diseases. In the study, we employed in vivo differentiated mature tissue mast cells freshly isolated from rat peritoneal cavity. Here, we demonstrated that rat peritoneal mast cells (rPMCs) express viral dsRNA-specific TLR3 molecule (intracellularly and on the cell surface) as well as other proteins associated with cellular antiviral response: IRF3, type I and II IFN receptors, and MHC I. We found that exposure of rPMCs to viral dsRNA mimic, i.e., poly(I:C), induced transient upregulation of surface TLR3 (while temporarily decreased TLR3 intracellular expression), type II IFN receptor, and MHC I. TLR3 ligand-stimulated rPMCs did not degranulate but generated and/or released type I IFNs (IFN-α and IFNβ) as well as proinflammatory lipid mediators (cysLTs), cytokines (TNF, IL-1β), and chemokines (CCL3, CXCL8). We documented that rPMC priming with poly(I:C) did not affect FcεRI-dependent degranulation. However, their costimulation with TLR3 agonist and anti-IgE led to a significant increase in cysLT and TNF secretion. Our findings confirm that MCs may serve as active participants in the antiviral immune response. Presented data on modulated FcεRI-mediated MC secretion of mediators upon poly(I:C) treatment suggests that dsRNA-type virus infection could influence the severity of allergic reactions.
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43

Sjoberg, Jan, Frida Schain, Ylva Tryselius, Linda Backman, Anna Porwit, Cheng Liu, Dawei Xu, et al. "Novel Findings Support a Patophysiological Role of the Arachidonic Cascade in Hodgkin Lymphoma." Blood 110, no. 11 (November 16, 2007): 2269. http://dx.doi.org/10.1182/blood.v110.11.2269.2269.

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Abstract Lipoxygenases (LO) are a family of structurally related enzymes which catalyze the conversion of the fatty acid arachidonic acid to biologically active metabolites. The key enzyme in leukotriene synthesis, 5- LO, catalyzes the first step in the metabolism of arachidonic acid to leukotriene (LT) C4. This compound and its metabolites LTD4 and LTE4, collectively called cysteinyl leukotrienes (cysLT), can bind to two high-affinity receptors, named cysLT1 and cysLT2. A sister enzyme to 5-LO is 15-LO-1 which also can catalyze the formation of bioactive metabolites. Arachidonic acid metabolites have traditionally been linked to inflammation and asthma but several studies also indicate a role of these metabolites in carcinogenesis In our studies of arachidonic acid metabolism in human lymphomas, we have identified the expression of 15-LO-1 and receptors for cysLT in primary as well as cultured Hodgkin-Reed Sternberg (H-RS) cells. In tumor tissue, H-RS cells positive for 15-LO-1 and the cysLT1 receptor were detected immunohistochemically in 13/15 and 12/16 cases, respectively. The presence of mRNA for 15-LO-1 and the cysLT1 and 2 receptors was confirmed by microarray analysis of laser dissected H-RS cells. Studies of 15-LO-1 gene transcription revealed that STAT6 activation and chromatin remodeling by DNA demethylation and histone acetylation are crucial for transcriptional activation of this gene in cultured H-RS cells. Incubation of the Hodgkin lymphoma-derived cell lines KMH2 and L1236 with LTD4 led to a robust calcium response that was completely abolished in presence of the cysLT1 receptor inhibitor zafirlukast. In L1236 cells, LTD4 induced increased DNA synthesis, interleukin-13 transcription and release of TNF-alpha, interleukin-6 and interleukin-8 in a dose-dependent manner, all of which were inhibited by zafirlukast. Thus, as the H-RS cells lack the expression of 5-LO, we hypothesize that that tumor-associated cysLT-producing inflammatory cells, such as eosinophils and mast cells, contribute to the pathogenesis of Hodgkin lymphoma through induction of tumor cell proliferation and cytokine release. Furthermore, immunohistochemical studies of 20 non-Hodgkin lymphomas revealed the expression of cysLT1 receptors also in primary mediastinal B cell lymphomas (PMBCL), and the functionality of these receptors was confirmed in the PMBCL-derived cell line MedB1. Taken together, these novel findings support a role for arachidonic acid metabolites in the pathogenesis of lymphoma.
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44

Matsuse, Hiroto, Hiroko Hirose, Susumu Fukahori, Tomoko Tsuchida, Shinya Tomari, Tetsuya Kawano, Chizu Fukushima, and Shigeru Kohno. "Regulation of Dendritic Cell Functions against Harmful Respiratory Pathogens by a Cysteinyl Leukotrienes Receptor Antagonist." Allergy & Rhinology 3, no. 1 (January 2012): ar.2012.3.0021. http://dx.doi.org/10.2500/ar.2012.3.0021.

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Cysteinyl leukotriene receptor antagonist (LTRA) is a widely used medicine for asthma. Cysteinyl leukotrienes (cysLTs) are involved in the regulation of dendritic cell (DC) function. However, the effects of LTRA on DC-related antimicrobial immunity against harmful respiratory pathogens remain unknown. The purpose of this study was to examine the effects of LTRA administered in vivo on DC function against representative respiratory pathogens in vitro. Pulmonary DCs were isolated from four groups of mice: control, mite allergen sensitized (AS), and AS mice treated with the corticosteroid dexamethasone (Dex) or with the LTRA pranlukast (Prl). These DCs were incubated with mite allergen, lipopolysaccharide (LPS), Aspergillus fumigatus, or respiratory syncytial virus (RSV). IL-10 and IL-12 production was then determined. Dex treatment significantly inhibited lipopolysaccharide (LPS)-induced IL-10 and IL-12 production as well as baseline IL-12 production in AS mice. The Prl did not significantly inhibit LPS-induced IL-10 and IL-12 production in AS mice. More importantly, Prl significantly increased IL-10 and IL-12 in AS mice after RSV infection. This study shows that LTRA that is used for asthma potentially up-regulates antimicrobial immunity through modulation of DC function against some respiratory infections without immunosuppression.
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Sasaki, Kazutoyo, Nobuaki Mizutani, Takeshi Nabe, Hiroshi Takenaka, and Shigekatu Kohno. "Studies on the experimental allergic rhinitis induced by the Japanese cedar pollen. XVIII. The role of CysLTs in nasal blockage and eosinophilia." Japanese Journal of Pharmacology 79 (1999): 58. http://dx.doi.org/10.1016/s0021-5198(19)34255-6.

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46

Rovati, G. Enrico, and Valérie Capra. "Cysteinyl-Leukotriene Receptors and Cellular Signals." Scientific World JOURNAL 7 (2007): 1375–92. http://dx.doi.org/10.1100/tsw.2007.185.

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Cysteinyl-leukotrienes (cysteinyl-LTs) exert a range of proinflammatory effects, such as constriction of airways and vascular smooth muscle, increase of endothelial cell permeability leading to plasma exudation and edema, and enhanced mucus secretion. They have proved to be important mediators in asthma, allergic rhinitis, and other inflammatory conditions, including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. The classification into subtypes of the cysteinyl-LT receptors (CysLTRs) was based initially on binding and functional data, obtained using the natural agonists and a wide range of antagonists. CysLTRs have proved remarkably resistant to cloning. However, in 1999 and 2000, the CysLT1R and CysLT2R were successfully cloned and both shown to be members of the G-protein coupled receptors (GPCRs) superfamily. Molecular cloning has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Recombinant CysLTRs couple to the Gq/11pathway that modulates inositol phospholipids hydrolysis and calcium mobilization, whereas in native systems, they often activate a pertussis toxin-insensitive Gi/o-protein, or are coupled promiscuously to both G-proteins. Interestingly, recent data provide evidence for the existence of an additional receptor subtype that seems to respond to both cysteinyl-LTs and uracil nucleosides, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Finally, a cross-talk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize recent data derived from studies on the molecular and cellular pharmacology of CysLTRs.
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47

Riley, Jason P., Barbara Fuchs, Lisa Sjöberg, Gunnar P. Nilsson, Lars Karlsson, Sven-Erik Dahlén, Navin L. Rao, and Mikael Adner. "Mast cell mediators cause early allergic bronchoconstriction in guinea-pigs in vivo: a model of relevance to asthma." Clinical Science 125, no. 11 (July 25, 2013): 533–42. http://dx.doi.org/10.1042/cs20130092.

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One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum injection and challenged with aerosolized OVA on day 14. On day 15, airway resistance was assessed after challenge with OVA or MCh (methacholine) using the forced oscillation technique, and lung tissue was prepared for histology. The contribution of mast cell mediators was investigated using inhibitors of the main mast cell mediators [histamine (pyrilamine) and CysLTs (cysteinyl-leukotrienes) (montelukast) and prostanoids (indomethacin)]. OVA-sensitized and challenged animals demonstrated AHR (airway hyper-responsiveness) to MCh, and lung tissue eosinophilic inflammation. Antigen challenge induced a strong EAR in the sensitized animals. Treatment with a single compound, or indomethacin together with pyrilamine or montelukast, did not reduce the antigen-induced airway resistance. In contrast, dual treatment with pyrilamine together with montelukast, or triple inhibitor treatment, attenuated approximately 70% of the EAR. We conclude that, as in humans, the guinea-pig allergic inflammation model exhibits both EAR and AHR, supporting its suitability for in vivo identification of mast cell mediators that contribute to the development of asthma. Moreover, the known mast cell mediators histamine and leukotrienes were major contributors of the EAR. The data also lend further support to the concept that combination therapy with selective inhibitors of key mediators could improve asthma management.
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48

Priyadharshini, V. S., Marcos Alejandro Jiménez-Chobillon, Jos de Graaf, Raúl Porras Gutiérrez de Velasco, Christina Gratziou, Fernando Ramírez-Jiménez, and Luis M. Teran. "Transcriptome Analysis Identifies Doublesex and Mab-3 Related Transcription Factor (DMRT3) in Nasal Polyp Epithelial Cells of Patients Suffering from Non-Steroidal Anti-Inflammatory Drug-Exacerbated Respiratory Disease (AERD)." Biomolecules 11, no. 8 (July 23, 2021): 1092. http://dx.doi.org/10.3390/biom11081092.

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Background: Aspirin-exacerbated respiratory disease (AERD) is a syndrome characterised by chronic rhinosinusitis, nasal polyps, asthma and aspirin intolerance. An imbalance of eicosanoid metabolism with anover-production of cysteinyl leukotrienes (CysLTs) has been associated with AERD. However, the precise mechanisms underlying AERD are unknown. Objective: To establish the transcriptome of the nasal polyp airway epithelial cells derived from AERD patients to discover gene expression patterns in this disease. Methods: Nasal airway epithelial cells were isolated from 12 AERD polyps and 8 AERD non-polyp nasal mucosa samples as controls from the same subjects. Utilising the Illumina HiSeq 2500 platform, RNA samples were sequenced. Potential gene candidate DMRT3 was selected from the differentially-expressed genes for validation. Results: Comparative transcriptome profiling of nasal epithelial cells was accomplished in AERD. A total of 20 genes had twofold mean regulation expression differences or greater. In addition, 8 genes were upregulated, including doublesex and mab-3 related transcription factor 3 (DMRT3), and 12 genes were downregulated. Differentially regulated genes comprised roles in inflammation, defence and immunity. Metabolic process and embryonic development pathways were significantly enriched. Enzyme-linked immune sorbent assay (ELISA) results of DMRT3 in AERD patients were significantly upregulated compared to controls (p = 0.03). Immunohistochemistry (IHC) of AERD nasal polyps localised DMRT3 and was predominantly released in the airway epithelia. Conclusion: Findings suggest that DMRT3 could be potentially involved in nasal polyp development in AERD patients. Furthermore, several genes are downregulated, hinting at the dedifferentiation phenomenon in AERD polyps. However, further studies are imperative to confirm the exact mechanism of polyp formation in AERD patients.
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Guimarães, Francielle Rodrigues, Helioswilton Sales-Campos, Viviani Nardini, Thiago Alvares da Costa, Monique Thaís Costa Fonseca, Virmondes Rodrigues Júnior, Carlos Artério Sorgi, et al. "The inhibition of 5-Lipoxygenase (5-LO) products leukotriene B4 (LTB 4 ) and cysteinyl leukotrienes (cysLTs) modulates the inflammatory response and improves cutaneous wound healing." Clinical Immunology 190 (May 2018): 74–83. http://dx.doi.org/10.1016/j.clim.2017.08.022.

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50

Żelechowska, Paulina, Ewa Brzezińska-Błaszczyk, Sylwia Różalska, Justyna Agier, and Elżbieta Kozłowska. "Native and IgE-primed rat peritoneal mast cells exert pro-inflammatory activity and migrate in response to yeast zymosan upon Dectin-1 engagement." Immunologic Research 69, no. 2 (March 11, 2021): 176–88. http://dx.doi.org/10.1007/s12026-021-09183-7.

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AbstractMast cells (MCs) play an essential role in host defense, primarily because of their location, their ability to pathogen destruction via several mechanisms, and the pattern recognition receptors they express. Even though most data is available regarding MC activation by various bacteria- or virus-derived molecules, those cells’ activity in response to constituents associated with fungi is not recognized enough. Our research aimed to address whether Saccharomyces cerevisiae-derived zymosan, i.e., β-(1,3)-glucan containing mannan particles, impacts MC activity aspects. Overall, the obtained results indicate that zymosan has the potential to elicit a pro-inflammatory response of rat peritoneal MCs. For the first time ever, we provided evidence that zymosan induces fully mature MC migration, even in the absence of extracellular matrix (ECM) proteins. Moreover, the zymosan-induced migratory response of MCs is almost entirely a result of directional migration, i.e., chemotaxis. We found that zymosan stimulates MCs to degranulate and generate lipid mediators (cysLTs), cytokines (IFN-α, IFN-β, IFN-γ, GM-CSF, TNF), and chemokine (CCL2). Zymosan also upregulated mRNA transcripts for several cytokines/chemokines with pro-inflammatory/immunoregulatory activity. Moreover, we documented that zymosan activates MCs to produce reactive oxygen species (ROS). Lastly, we established that the zymosan-induced MC response is mediated through activation of the Dectin-1 receptor. In general, our results strongly support the notion that MCs contribute to innate antifungal immunity and bring us closer to elucidate their role in host-pathogenic fungi interactions. Besides, provided findings on IgE-sensitized MCs appear to indicate that exposure to fungal zymosan could affect the severity of IgE-dependent disorders, including allergic ones.
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