title: Role of EP2 and EP4 receptors  in airway microvascular leak  induced by prostaglandin E2.
abstract: OBJECTIVE
  Airway microvascular leak (MVL) involves the extravasation of proteins from post-capillary venules into surrounding tissue. MVL is a cardinal sign of inflammation and an important feature of airway inflammatory diseases such as asthma. PGE2, a product of COX-mediated metabolism of arachidonic acid, binds to four receptors, termed EP1–4. PGE2 has a wide variety of effects within the airway, including modulation of inflammation, sensory nerve activation and airway tone. However, the effect of PGE2 on airway MVL and the receptor/s that mediate this have not been described.
  
  
  METHODS
  Evans Blue dye was used as a marker of airway MVL, and selective EP receptor agonists and antagonists were used alongside EP receptor-deficient mice to define the receptor subtype involved.
  
  
  RESULTS
  PGE2 induced significant airway MVL in mice and guinea pigs. A significant reduction in PGE2-induced MVL was demonstrated in Ptger2−/− and Ptger4−/− mice and in wild-type mice pretreated simultaneously with EP2 (PF-04418948) and EP4 (ER-819762) receptor antagonists. In a model of allergic asthma, an increase in airway levels of PGE2 was associated with a rise in MVL; this change was absent in Ptger2−/− and Ptger4−/− mice.
  
  
  CONCLUSIONS
  PGE2 is a key mediator produced by the lung and has widespread effects according to the EP receptor activated. Airway MVL represents a response to injury and under ‘disease’ conditions is a prominent feature of airway inflammation. The data presented highlight a key role for EP2 and EP4 receptors in MVL induced by PGE2.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Jones
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Maher
authors.forename: Mark
authors.initials: M
authors.lastname: Griffiths
authors.forename: Megan
authors.initials: M
authors.lastname: Grace
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Donnell
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Clark
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
mesh_terms: D000485:Allergens; D000818:Animals; D001249:Asthma / Q000378:metabolism*; D001384:Azetidines / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D001980:Bronchi / Q000378:metabolism; D002199:Capillary Permeability; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism
chemical_list: C499423:9-deoxy-9-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydroprostaglandin E2; D000485:Allergens; D001384:Azetidines; D001552:Benzazepines; C549634:ER 819762; D007093:Imidazoles; D008738:Methyl Ethers; C121546:ONO AE 248; C461399:ONO-AE1-329; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D010047:Ovalbumin; C570688:1-(4-fluorobenzoyl)-3-(((6-methoxy-2-naphthyl)oxy)methyl)azetidine-3-carboxylic acid; D015232:Dinoprostone