title: An endothelin receptor antagonist, SB-217242, inhibits airway hyperresponsiveness in allergic mice.
abstract: Within the airways, endothelin-1 (ET-1) can exert a range of prominent effects, including airway smooth muscle contraction, bronchial obstruction, airway wall edema, and airway remodeling. ET-1 also possesses proinflammatory properties and contributes to the late-phase response in allergic airways. However, there is no direct evidence for the contribution of endogenous ET-1 to airway hyperresponsiveness in allergic airways. Allergic inflammation induced in mice by sensitization and challenge with the house dust mite allergen Der P1 was associated with elevated levels of ET-1 within the lung, increased numbers of eosinophils within bronchoalveolar lavage fluid and tissue sections, and development of airway hyperresponsiveness to methacholine (P < 0.05, n = 6 mice per group). Treatment of allergic mice with an endothelin receptor antagonist, SB-217242 (30 mg x kg(-1) x day(-1)), during allergen challenge markedly inhibited airway eosinophilia (bronchoalveolar lavage fluid and tissue) and development of airway hyperresponsiveness. These findings provide direct evidence for a mediator role for ET-1 in development of airway hyperresponsiveness and airway eosinophilia in Der P1-sensitized mice after antigen challenge.
authors.affiliation: Department of Pharmacology, University of Western Australia, Crawley 6009, Australia. phenry@receptor.pharm.uwa.edu.au
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Henry
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Mann
authors.forename: Angela C
authors.initials: AC
authors.lastname: D'Aprile
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Self
authors.forename: Roy G
authors.initials: RG
authors.lastname: Goldie
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002264:Carboxylic Acids / Q000494:pharmacology*; D002452:Cell Count; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology; D006967:Hypersensitivity / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D007189:Indans / Q000494:pharmacology*; D007958:Leukocyte Count; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA
chemical_list: D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007189:Indans; C098288:enrasentan