Cyclooxygenase activity in bradykinin-induced dermal extravasation. A study in mice and humans

Graphical illustration of the potential role of prostaglandin formation for dermal extravasation induced by activation of bradykinin type 2 receptors (B2). B2 translates the bradykinin signal via the Gq transduction pathway including generation of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) resulting in an increase of the intracellular concentration of Ca2+. This ion binds and activates a variety of intracellular proteins. Among those, binding to calmodulin is an essential step to activate endothelial NO synthase (eNOS), while binding to phospholipase A2 (PLA2) directly stimulates this enzyme to release arachidonic acid (AA) from the cell membrane and initiates the generation of PGH2 by cyclooxygenases (COX). This prostaglandin functions as a substrate for a variety of prostaglandin synthases (PG-S) finally resulting in formation of specific prostaglandins. Once synthetized, these lipid mediators are released by the producing endothelial cell into small dermal blood vessel and activate their receptors located either in the producing cell (autocrine), or in adjacent cells (paracrine) or both. This activation of endothelial prostaglandin receptors might contribute to bradykinin induced extravasation, i.e. the increase of fluid transfer to the interstitial space (red intravascular dots indicate red blood cells). [Display omitted] •Non-allergic angioedema is driven by bradykinin and potentially life-threatening.•Here, dermal bradykinin was shown to signal via prostaglandin but not NO formation in mice.•Likewise, dermal bradykinin was shown to signal via prostaglandin formation in humans.•These results may pave the way for new treatment options for severe ACE inhibitor-induced angioedema.•Our findings may also provide a rationale for the use of glucocorticoids in severe cases of non-allergic angioedema. Non-allergic angioedema is largely driven by increased plasma levels of bradykinin and over-activation of bradykinin receptor type II (B2), but the specific downstream signalling pathways remain unclear. The aim of this study was to identify signal transduction events involved in bradykinin-induced dermal extravasation. Quantification of dermal extravasation was accomplished following intradermal (i.d.) injection of bradykinin or the B2 agonist labradimil in mice with endothelial NO-synthase (eNOS) deficiency and in C57BL/6J mice pre-treated with vehicle, NO-synthase or cyclooxygenase (COX) inhibitors. In the multicentre clinical study ABRASE, 38