title: Prostaglandin E2 inhibits mast cell-dependent bronchoconstriction in human small airways through the E prostanoid subtype 2 receptor.
abstract: BACKGROUND
  Inhaled prostaglandin (PG) E2 might inhibit asthmatic responses, but the mechanisms involved remain undefined.
  
  
  OBJECTIVE
  We sought to characterize the direct and indirect effects of PGE2 on human small airways with particular reference to the receptors mediating the responses.
  
  
  METHODS
  Contraction and relaxation were studied in isolated human bronchi with an inner diameter of 1 mm or less.
  
  
  RESULTS
  Low concentrations of PGE2 (0.01-1 μmol/L) relaxed the bronchi precontracted by histamine. The bronchodilator response was inhibited by the E prostanoid (EP) subtype 4 receptor antagonist ONO-AE3-208 but unaffected by the EP2 receptor antagonist PF-04418948. Higher concentrations of PGE2 (10-100 μmol/L) contracted the small airways. However, the TP receptor agonists U-46,619, PGF2α, and PGD2 were more potent than PGE2. Moreover, the bronchoconstrictor responses to PGE2 and all other tested prostanoids, including the EP1/EP3 receptor agonist 17-phenyl trinor PGE2 and the partial FP receptor agonist AL-8810, were uniformly abolished by the TP receptor antagonist SQ-29,548. In the presence of TP and EP4 antagonists, PGE2 inhibited the mast cell-mediated bronchoconstriction resulting from anti-IgE challenge. Measurement of the release of histamine and cysteinyl leukotrienes documented that this bronchoprotective action of PGE2 was mediated by the EP2 receptor, unrelated to bronchodilation, and increased with time of exposure.
  
  
  CONCLUSIONS
  The pharmacology of PGE2 in isolated human small airways was different from its profile in animal models. This first demonstration of powerful EP2 receptor-mediated inhibition of IgE-dependent contractions in human airways introduces a new selective target for the treatment of asthma. This EP2 control of mast cell-mediated bronchoconstriction is presumably exaggerated in patients with aspirin-exacerbated respiratory disease.
authors.affiliation: Unit for Experimental Asthma and Allergy Research, Institute of Environmental Medicine, and the Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden. Electronic address: jesper.safholm@ki.se.
authors.forename: Jesper
authors.initials: J
authors.lastname: Säfholm
authors.affiliation: Unit for Experimental Asthma and Allergy Research, Institute of Environmental Medicine, and the Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martijn L
authors.initials: ML
authors.lastname: Manson
authors.affiliation: Unit for Experimental Asthma and Allergy Research, Institute of Environmental Medicine, and the Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Bood
authors.affiliation: Unit for Experimental Asthma and Allergy Research, Institute of Environmental Medicine, and the Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Delin
authors.affiliation: Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Orre
authors.affiliation: Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery (MMK), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Bergman
authors.affiliation: Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Mamdoh
authors.initials: M
authors.lastname: Al-Ameri
authors.affiliation: Unit for Experimental Asthma and Allergy Research, Institute of Environmental Medicine, and the Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
authors.affiliation: Unit for Experimental Asthma and Allergy Research, Institute of Environmental Medicine, and the Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D001384:Azetidines / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016084:Bronchoconstriction / Q000187:drug effects; D002478:Cells, Cultured; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007073:Immunoglobulin E / Q000276:immunology; D066298:In Vitro Techniques; D008407:Mast Cells / Q000276:immunology*; D058990:Molecular Targeted Therapy; D009281:Naphthalenes / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000819:agonists; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000819:agonists; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors
chemical_list: C092396:17-phenyltrinorprostaglandin E2; C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D009281:Naphthalenes; C545650:PTGER4 protein, human; D010654:Phenylbutyrates; D011982:Receptors, Prostaglandin; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D017482:Receptors, Thromboxane; C034671:prostaglandin F2alpha receptor; C121227:AL 8810; D007073:Immunoglobulin E; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006632:Histamine; C045749:SQ 29548; D015237:Dinoprost; C570688:1-(4-fluorobenzoyl)-3-(((6-methoxy-2-naphthyl)oxy)methyl)azetidine-3-carboxylic acid; D015232:Dinoprostone; D015230:Prostaglandin D2
keywords: Aspirin-exacerbated respiratory disease; COX products; E prostanoid receptor; asthma; explanted human tissue model; human bronchi; pharmacologic testing; prostanoid receptors; thromboxane receptor