Effects of a Cysteinyl Leukotriene Dual 1/2 Receptor Antagonist on Antigen-Induced Airway Hypersensitivity and Airway Inflammation in a Guinea Pig Asthma Model

Muraki, Masato; Imbe, Shu; Santo, Hiroshi; Sakakibara, Ryuji; Sano, Hiroyuki; Iwanaga, Takashi; Tohda, Yuji

doi:10.1159/000327439

Cited by 7 publications

(8 citation statements)

References 47 publications

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“…Eosinophils are equipped with receptors to recognize and quickly respond to immune cell- or pathogen-derived molecules [21]. Upon stimulation by chemotactic factors or chemokines, transmigrated eosinophils arrive in inflamed tissues and are further activated by the proinflammatory microenvironment, which leads to diverse cellular responses, such as adhesion to extracellular matrix proteins, neutrophils or T cells, degranulation and production of cytokines, chemokines or cysteinyl leukotrienes [22,23,24].…”

Section: Introductionmentioning

confidence: 99%

NOX2-Derived ROS-Mediated Surface Translocation of BLT1 Is Essential for Exocytosis in Human Eosinophils Induced by LTB<sub>4</sub>

Min¹,

Lee²,

Kim³

et al. 2014

Int Arch Allergy Immunol

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Background: Leukotriene B₄ (LTB₄) is a proinflammatory lipid mediator that elicits eosinophil exocytosis, leading to allergic inflammation. However, the detailed intracellular signaling mechanisms of eosinophil exocytosis induced by LTB₄ are poorly understood. Herein, we report that NADPH oxidase (NOX)2-derived reactive oxygen species (ROS)-mediated BLT1 migration to the cell surface is required for exocytosis in human eosinophils induced by LTB₄. Methods: Peripheral blood eosinophils were purified and stimulated for up to 60 min with LTB₄. The signaling role of NOX2-derived ROS in BLT1-dependent exocytosis in LTB₄-stimulated eosinophils was investigated. Results: Stimulating eosinophils with LTB₄ induced intracellular ROS production and surface upregulation of the exocytosis marker protein CD63 via BLT1-mediated signaling. LTB₄ induced p47^phox phosphorylation and 91^phox expression required for NOX2 activation in a BLT1-dependent manner. Pretreatment with NOX2 inhibitors, but not mitochondria inhibitor, prevented LTB₄-induced ROS generation and exocytosis. At 30 min after stimulation with LTB₄, BLT1 expression at the cell surface was upregulated. LTB₄-triggered surface upregulation of BLT1 was also blocked by inhibition of ROS generation with NOX2 inhibitors. Moreover, stimulation for 30 min with LTB₄ resulted in the interaction of BLT1 with NOX2 by immunoprecipitation. LTB₄-induced ROS generation, surface upregulation of BLT1 and exocytosis was also inhibited by pretreatment with a lipid raft disruptor, protein kinase C inhibitor, or Src kinase inhibitor. Conclusion: These results suggest that NOX2-derived ROS-mediated BLT1 trafficking to the cell surface plays a key role in the exocytosis of human eosinophils induced by LTB₄.

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Section: Introductionmentioning

confidence: 99%

NOX2-Derived ROS-Mediated Surface Translocation of BLT1 Is Essential for Exocytosis in Human Eosinophils Induced by LTB<sub>4</sub>

Min¹,

Lee²,

Kim³

et al. 2014

Int Arch Allergy Immunol

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“…Although these forms of montelukast exert significant anti-asthmatic effects, they have not yet been marketed. Current LTRAs antagonize cysLT1R but not cysLT2R and since cysLT2R might be involved in the pathogenesis of asthma, the development and clinical application of dual antagonists might be a promising asthma treatment [98]. Besides cysLTs, antagonism of the LTB4 pathway is also of interest.…”

Section: Resultsmentioning

confidence: 99%

Leukotriene receptor antagonists pranlukast and montelukast for treating asthma

Matsuse

Kohno

2013

Expert Opinion on Pharmacotherapy

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IntroductionThe prevalence of bronchial asthma, which is a chronic inflammatory disorder of the airway, is increasing worldwide. Although inhaled corticosteroids (ICS) play a central role in the treatment of asthma, they cannot achieve good control for all asthmatics and medications such as leukotriene receptor antagonists (LTRAs) with bronchodilatory and anti-inflammatory effects often serve as alternatives or add-on drugs. Several issues such as predicted responses, effects of peripheral airway and airway remodeling and alternative administration routes remain to be clarified before LTRAs PAGE 3 could serve a more effective role in the treatment of asthma. Areas covered

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“…Male Hartley guinea pigs were sensitized with OVA (Sigma, St. Louis, MO) to generate an asthma model (Muraki et al, 2011). In brief, 4-week-old guinea pigs weighing 250-350 g were intraperitoneally administered the following: (1) 30 mg/kg of cyclophosphamide (Shionogi & Co., Ltd. Osaka, Japan); (2) 2 days later, 1 mg of OVA together with 100 mg aluminum hydroxide [Al(OH) 3 ] (Wako Pure Chemical Industries, Ltd. Osaka, Japan) and (3) 10 mg of OVA with 100 mg Al(OH) 3 as a booster, 3 weeks after the initial sensitization with OVA.…”

Section: Animals and Sensitizationmentioning

confidence: 99%

“…Airway reactivity was determined by monitoring enhanced pause (Penh) units obtained from a whole body plethysmograph (BioSystem XA; Buxco Electronics, Suita, Japan) that measures respiratory function in unrestrained animals (Muraki et al, 2011). Guinea pigs were individually placed into the body plethysmograph for data collection.…”

Section: Airway Reactivity To Ova or Achmentioning

confidence: 99%

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Effects of inhaled aminophylline on airway constriction and inflammation in ovalbumin-sensitized guinea pigs

Muraki¹,

Wada²,

Ohno³

et al. 2013

Drug Delivery

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Background: The systemic administration of theophylline is useful for asthma treatment. However its narrow therapeutic range makes it difficult to use. Little is known about its potential in inhalation therapy, particularly repeated inhalation. Objective: The purpose of this study is to investigate the therapeutic usefulness of inhaled aminophylline in an asthma model. Methods: The effects of pretreatment with inhaled aminophylline (25 mg/mL for 30 min/dose) on airway response and inflammation after an ovalbumin (OVA) challenge and airway hypersensitivity to acetylcholine (Ach) were evaluated using guinea pigs sensitized with OVA. Results: Aminophylline relaxed the ACh-induced contraction of tracheal smooth muscle in vitro in a concentration-dependent manner. Pretreatment with single-dose aminophylline inhalation suppressed OVA-induced airway constriction to the same extent as the intraperitoneal pretreatment with high-dose aminophylline (10-20 mg/kg). However, pretreatment with singledose aminophylline inhalation did not suppress eosinophil infiltration into airways (neither bronchoalveolar lavage [BAL] fluid nor lung tissue) and did not suppress airway hyperreactivity to ACh, 24 h after OVA challenge. Repeated inhalation of aminophylline (twice daily for 7 days) suppressed the infiltration of eosinophils and suppressed airway hypersensitivity to ACh. In addition, high concentrations of aminophylline inhibited production of oxygen radicals by BAL cells. Conclusion: Single-dose inhalation treatment with aminophylline has transient but relatively strong bronchodilating effects due to delivery of high doses into local airways. Repeated inhalation treatment suppressed airway inflammation and hypersensitivity induced by allergens. Therefore, inhaled aminophylline may be useful for asthma treatment.

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Effects of a Cysteinyl Leukotriene Dual 1/2 Receptor Antagonist on Antigen-Induced Airway Hypersensitivity and Airway Inflammation in a Guinea Pig Asthma Model

Cited by 7 publications

References 47 publications

NOX2-Derived ROS-Mediated Surface Translocation of BLT1 Is Essential for Exocytosis in Human Eosinophils Induced by LTB<sub>4</sub>

NOX2-Derived ROS-Mediated Surface Translocation of BLT1 Is Essential for Exocytosis in Human Eosinophils Induced by LTB<sub>4</sub>

Leukotriene receptor antagonists pranlukast and montelukast for treating asthma

Effects of inhaled aminophylline on airway constriction and inflammation in ovalbumin-sensitized guinea pigs

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