title: Activation of the Prostaglandin E2 receptor EP2 prevents house dust mite-induced airway hyperresponsiveness and inflammation by restraining mast cells' activity.
abstract: BACKGROUND
  Prostaglandin E2 (PGE2 ) has been proposed to exert antiasthmatic effects in patients, to prevent antigen-induced airway pathology in murine models, and to inhibit mast cells (MC) activity in vitro.
  
  
  OBJECTIVE
  To assess in a murine model whether the protective effect of PGE2 may be a consequence of its ability to activate the E-prostanoid (EP)2 receptor on airway MC.
  
  
  METHODS
  Either BALB/c or C57BL/6 mice were exposed intranasally (i.n.) to house dust mite (HDM) aeroallergens. Both strains were given PGE2 locally (0.3 mg/kg), but only BALB/c mice were administered butaprost (EP2 agonist: 0.3 mg/kg), or AH6809 (EP2 antagonist; 2.5 mg/kg) combined with the MC stabilizer sodium cromoglycate (SCG: 25 mg/kg). Airway hyperresponsiveness (AHR) and inflammation, along with lung MC activity, were evaluated. In addition, butaprost's effect was assessed in MC-mediated passive cutaneous anaphylaxis (PCA) in mice challenged with 2,4-dinitrophenol (DNP).
  
  
  RESULTS
  Selective EP2 agonism attenuated aeroallergen-caused AHR and inflammation in HDM-exposed BALB/c mice, and this correlated with a reduced lung MC activity. Accordingly, the blockade of endogenous PGE2 by means of AH6809 worsened airway responsiveness in sensitive BALB/c mice, and such worsening was reversed by SCG. The relevance of MC to PGE2 -EP2 driven protection was further highlighted in MC-dependent PCA, where butaprost fully prevented MC-induced ear swelling. Unlike in BALB/c mice, PGE2 did not protect the airways of HDM-sensitized C57BL/6 animals, a strain in which we showed MC to be irrelevant to aeroallergen-driven AHR and inflammation.
  
  
  CONCLUSIONS
  The beneficial effect of both exogenous and endogenous PGE2 in aeroallergen-sensitized mice may be attributable to the activation of the EP2 receptor, which in turn acts as a restrainer of airway MC activity. This opens a path towards the identification of therapeutic targets against asthma along the 'EP2 -MC-airway' axis.
authors.affiliation: Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Serra-Pages
authors.affiliation: Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.|CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain.|Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Torres
authors.affiliation: Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.|CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Plaza
authors.affiliation: Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Herrerias
authors.affiliation: Department of Surgery and Animals Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Costa-Farré
authors.affiliation: Department of Surgery and Animals Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Marco
authors.affiliation: Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.|CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Hepáticas y Digestivas.
authors.forename: M
authors.initials: M
authors.lastname: Jiménez
authors.affiliation: Department of Dermatology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Maurer
authors.affiliation: CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain.|Department of Pneumology and Respiratory Allergy, Hospital Clínic, IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Universitat de Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Picado
authors.affiliation: Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: de Mora
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D015232:Dinoprostone / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D039981:Pyroglyphidae; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000276:immunology*
chemical_list: D058307:Receptors, Prostaglandin E, EP2 Subtype; D015232:Dinoprostone
keywords: EP2 receptor; PGE2; allergy; asthma; house dust mite; mast cells