Abstract
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. 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.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 ResultsPGE2 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 and ImplicationsPGE2 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.
Highlights
Airway microvascular leakage (MVL) and plasma exudation represent classical features in the pathogenesis of various respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD) (Paredi and Barnes, 2009)
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
Summary
Airway microvascular leakage (MVL) and plasma exudation represent classical features in the pathogenesis of various respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD) (Paredi and Barnes, 2009). Many mediators (e.g. cysteinyl leukotrienes, histamine, bradykinin, 5-HT and cytokines) are capable of inducing this effect when released in response to an inflammatory insult in the airway, where they can act upon the endothelium of post-capillary venules to open these intercellular gaps This effect causes plasma to ‘leak’ out into extravascular sites because of hydrostatic pressure gradients (Olivenstein et al, 1997; Reynolds et al, 2002; Greiff et al, 2003). PGE2 is an endogenous lipid eicosanoid synthesized by COX-mediated metabolism of free arachidonic acid It is produced in a variety of cells, including airway smooth muscle, epithelial cells, alveolar macrophages and pulmonary endothelial cells (Meyrick et al, 1989; Widdicombe et al, 1989). The effect of PGE2 on airway MVL and the receptor/s that mediate this have not been described.
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