Role of Ep2 and Ep4 receptors in airway microvascular leak induced by prostaglandin E2.

Background and PurposeAirway 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 EP1-4. 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 ApproachEvans 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 ResultsPGE(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 EP2 (PF-04418948) and EP4 (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 ImplicationsPGE(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 EP2 and EP4 receptors in MVL induced by PGE(2.更多