Role of EP(2) and EP(4) receptors in airway microvascular leak induced by prostaglandin E(2)

BACKGROUND AND PURPOSE: 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. PGE(2), a product of COX‐mediated metabolism of arachidonic acid, binds to four receptors, termed EP(1–4). PGE(2) has a wide variety of effects within the airway, including modulation of inflammation, sensory nerve activation and airway tone. However, the effect of PGE(2) on airway MVL and the receptor/s that mediate this have not been described. EXPERIMENTAL APPROACH: 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. KEY RESULTS: PGE(2) induced significant airway MVL in mice and guinea pigs. A significant reduction in PGE(2)‐induced MVL was demonstrated in Ptger2 (−/−) and Ptger4 (−/−) mice and in wild‐type mice pretreated simultaneously with EP(2) (PF‐04418948) and EP(4) (ER‐819762) receptor antagonists. In a model of allergic asthma, an increase in airway levels of PGE(2) was associated with a rise in MVL; this change was absent in Ptger2 (−/−) and Ptger4 (−/−) mice. CONCLUSIONS AND IMPLICATIONS: PGE(2) 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 EP(2) and EP(4) receptors in MVL induced by PGE(2.)