Role of EP₂ and EP₄ receptors in airway microvascular leak induced by prostaglandin E₂

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.

Mass spectrometry profiling of oxylipins, endocannabinoids, and N-acylethanolamines in human lung lavage fluids reveals responsiveness of prostaglandin E2 and associated lipid metabolites to biodiesel exhaust exposure

“…Bronchial epithelial cell-derived PGE 2 has also been shown to dampen the reactivity of dendritic cells [56]. However, in a recent paper, it was shown that PGE 2 induced significant airway microvascular leak in mice and guinea pigs that was mediated via activation of the EP2 and EP4 receptors, implying destructive effects of PGE 2 [57]. The intricate function of PGE 2 is only one example of the complexity of an adequate inflammatory response that, besides PGE 2 , also involves other studied eicosanoids and associated bioactive lipid mediators that altogether exhibit coordinated and often opposing actions [22].…”

Selectively targeting prostanoid E (EP) receptor-mediated cell signalling pathways: Implications for lung health and disease

“…Since that time, these mice have been used in a number of key studies that provide notable in vivo proof-of-concept data. For example, prostanoid receptor-deficient transgenic mice have been used to show that EP4 receptor activation is responsible for the antiinflammatory activity of PGE2 [98] and to implicate EP2 and EP4 receptors in PGE2-induced microvascular leak [99]. Further studies that utilize these mice are warranted.…”

“…Moreover microvascular leak has also been shown to exist in COPD [105]. In 2016, Jones et al [99] utilized mouse and guinea pig allergic asthma models to demonstrate the influence of EP2 and EP4 receptors on microvascular leakage. Activating the EP2 and EP4 receptors with PGE2, or selective agonists ONO-AE1-259 (EP2) and ONO-AE1-329 (EP4) induces microvascular leakage.…”

Prolonged activation of cAMP signaling leads to endothelial barrier disruptionviatranscriptional repression ofRRAS

“…PGE2 is a proinflammatory lipid that binds to and activates GPCRs, such as EP 4 , and increases cAMP production by activating AC (39,40). PGE2 is known to increase vascular permeability (41)(42)(43) as well as angiogenesis (44). We first studied the EP 4 expression levels in HUVECs, HDMECs, and HBECs to evaluate their responsiveness upon PGE2 stimulation.…”