Regulatory role of PGE2 and EP receptors in pulmonary endothelial cell function

During inflammation, prostaglandin E2 (PGE2) is abundantly secreted by fibroblasts, monocytes, endothelial and epithelial cells. PGE2 activates four distinct E-type prostanoid (EP1-4) receptors giving rise to often opposing cellular effects. Most of our knowledge regarding the biological roles of PGE2 is based on experiments using cyclooxygenase (COX) inhibitors, which also inhibit the release of other prostanoids. The proposed study aims to unravel the molecular and cellular mechanisms by which PGE2 and it receptors regulate pulmonary microvascular barrier function. Most importantly, we will investigate how selective EP agonists and/or antagonists might be exploited therapeutically to modulate endothelial function in conditions with increased microvascular permeability such as acute lung injury (ALI) using in vitro human cell systems and mouse models of ALI. The impact of PGE2 and EP receptors on vascular leakage and neutrophil recruitment in lungs will also be determined using EP receptor deficient mice. Our results from preparatory experiments hold great promise that the proposed study will establish novel therapeutic approaches using selective EP ligands for diseases with increased vascular permeability and neutrophil extravasation.

This project set out to investigate how PGE2 and its receptors regulate lung function with major focus on the vessel-forming endothelial cells. In course of the study we extended our investigations to the crosstalk of endothelial and epithelial cells in the lung as well as to the recently described immune cells, the innate lymphoid cells. We found that PGE2 and the EP1 / EP3 receptor agonist 17-pt-PGE2 via the EP4 receptor strengthened the endothelial barrier function. Additionally, we studied the role of PGE2 in alveolar epithelial and lung microvascular endothelial crosstalk. We demonstrated that the epithelial cell-derived PGE2 is a key regulator of endothelial barrier integrity via EP4 receptors under physiologic and inflammatory conditions. In the last part of the project we focused on the allergic inflammation-associated group 2 innate lymphoid cells (ILC2). We showed that PGE2 suppressed the function of ILC2. We can conclude that PGE2 plays protective roles in the lung by acting on the EP4 receptor of the endothelial cells during inflammatory conditions. Furthermore, PGE2 inhibits the function of ILC2 during allergic inflammation by activating EP2 and EP4 receptors. These results suggest promising therapeutic applications of EP2 and EP4 agonists in pulmonary diseases.