title: Prostaglandin E2 prevents hyperosmolar-induced human mast cell activation through prostanoid receptors EP2 and EP4.
abstract: BACKGROUND
  Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB.
  
  
  OBJECTIVE
  This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction.
  
  
  METHODS
  We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP(1-4) were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed.
  
  
  RESULTS
  Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP(2) and EP(4) receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone.
  
  
  CONCLUSIONS
  Our data show a protective role for the PGE2 receptors EP(2) and EP(4) following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition.
authors.affiliation: Unidad de Farmacología, Facultad de Medicina, Universidad de Panamá, Panama, Panama Republic; Laboratori d'Immunoal·lèrgia Respiratòria Clínica i Experimental, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Torres-Atencio
authors.affiliation: Laboratori d'Immunoal·lèrgia Respiratòria Clínica i Experimental, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Unitat de Bioquímica i Biologia Molecular, Department de Ciències Fisològiques I, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Erola
authors.initials: E
authors.lastname: Ainsua-Enrich
authors.affiliation: Department de Farmacologia, Terapéutica i Toxicologia, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: de Mora
authors.affiliation: Laboratori d'Immunoal·lèrgia Respiratòria Clínica i Experimental, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Picado
authors.affiliation: Laboratori d'Immunoal·lèrgia Respiratòria Clínica i Experimental, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Unitat de Bioquímica i Biologia Molecular, Department de Ciències Fisològiques I, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Martín
mesh_terms: D001250:Asthma, Exercise-Induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015550:Cell Degranulation; D002460:Cell Line; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D004234:Diuretics, Osmotic / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008353:Mannitol / Q000494:pharmacology; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D009997:Osmotic Pressure; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism*
chemical_list: D004234:Diuretics, Osmotic; C545644:PTGER2 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D008353:Mannitol; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone