Activation of the Prostaglandin E2 receptor EP2 prevents house dust mite-induced airway hyperresponsiveness and inflammation by restraining mast cells' activity

M. Serra-Pages, R. Torres, J. Plaza, A. Herrerias, C. Costa-Farré, A. Marco, M. Jiménez, M. Maurer, C. Picado, F. de Mora

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16 Citations (Scopus)

Abstract

© 2015 John Wiley & Sons Ltd. Background: Prostaglandin E<inf>2</inf> (PGE<inf>2</inf>) 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 PGE<inf>2</inf> may be a consequence of its ability to activate the E-prostanoid (EP)<inf>2</inf> 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 PGE<inf>2</inf> locally (0.3 mg/kg), but only BALB/c mice were administered butaprost (EP<inf>2</inf> agonist: 0.3 mg/kg), or AH6809 (EP<inf>2</inf> 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 EP<inf>2</inf> 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 PGE<inf>2</inf> by means of AH6809 worsened airway responsiveness in sensitive BALB/c mice, and such worsening was reversed by SCG. The relevance of MC to PGE<inf>2</inf>-EP<inf>2</inf> driven protection was further highlighted in MC-dependent PCA, where butaprost fully prevented MC-induced ear swelling. Unlike in BALB/c mice, PGE<inf>2</inf> 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 & Clinical Relevance: The beneficial effect of both exogenous and endogenous PGE<inf>2</inf> in aeroallergen-sensitized mice may be attributable to the activation of the EP<inf>2</inf> 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 'EP<inf>2</inf> -MC-airway' axis.
Original languageEnglish
Pages (from-to)1590-1600
JournalClinical and Experimental Allergy
Volume45
Issue number10
DOIs
Publication statusPublished - 1 Jan 2015

Keywords

  • Allergy
  • Asthma
  • EP2 receptor
  • House dust mite
  • Mast cells
  • PGE2

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