title: CysLT2receptor activation is involved in LTC4-induced lung air-trapping in guinea pigs.
abstract: CysLT1receptors are known to be involved in the pathogenesis of asthma. However, the functional roles of CysLT2receptors in this condition have not been determined. The purpose of this study is to develop an experimental model of CysLT2receptor-mediated LTC4-induced lung air-trapping in guinea pigs and use this model to clarify the mechanism underlying response to such trapping. Because LTC4is rapidly converted to LTD4by γ-glutamyltranspeptidase (γ-GTP) under physiological conditions, S-hexyl GSH was used as a γ-GTP inhibitor. In anesthetized artificially ventilated guinea pigs with no S-hexyl GSH treatment, i.v. LTC4-induced bronchoconstriction was almost completely inhibited by montelukast, a CysLT1receptor antagonist, but not by BayCysLT2RA, a CysLT2receptor antagonist. The inhibitory effect of montelukast was diminished by treatment with S-hexyl GSH, whereas the effect of BayCysLT2RA was enhanced with increasing dose of S-hexyl GSH. Macroscopic and histological examination of lung tissue isolated from LTC4-/S-hexyl-GSH-treated guinea pigs revealed air-trapping expansion, particularly at the alveolar site. Inhaled LTC4in conscious guinea pigs treated with S-hexyl GSH increased both airway resistance and airway hyperinflation. On the other hand, LTC4-induced air-trapping was only partially suppressed by treatment with the bronchodilator salmeterol. Although montelukast inhibition of LTC4-induced air-trapping was weak, treatment with BayCysLT2RA resulted in complete suppression of this air-trapping. Furthermore, BayCysLT2RA completely suppressed LTC4-induced airway vascular hyperpermeability. In conclusion, we found in this study that CysLT2receptors mediate LTC4-induced bronchoconstriction and air-trapping in S-hexyl GSH-treated guinea pigs. It is therefore believed that CysLT2receptors contribute to asthmatic response involving air-trapping.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Osaka, Japan. Electronic address: sekioka@ono.co.jp.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sekioka
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kadode
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yonetomi
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kamiya
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Department of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nabe
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawabata
mesh_terms: D000388:Air; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006168:Guinea Pigs; D017997:Leukotriene C4 / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D010795:Phthalic Acids / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000378:metabolism*; D012121:Respiration, Artificial; D000068299:Salmeterol Xinafoate / Q000494:pharmacology
chemical_list: C569223:3-(((3-carboxycyclohexyl)amino)carbonyl)-4-(3-(4-(4-phenoxybutoxy)phenyl)propoxy)benzoic acid; D003509:Cyclohexanecarboxylic Acids; D010795:Phthalic Acids; D018077:Receptors, Leukotriene; D017997:Leukotriene C4; D000068299:Salmeterol Xinafoate; C412375:cysteinyl leukotriene receptor 2; D005978:Glutathione; C033550:hexylglutathione
keywords: Air-trapping; Asthma; Bronchoconstriction; CysLT(1) receptors; CysLT(2) receptors; Cysteinyl leukotrienes