Contribution of cyclooxygenase-1-dependent prostacyclin synthesis to bradykinin-induced dermal extravasation.

BACKGROUND: Non-allergic angioedema is a potentially life-threatening condition caused by accumulation of bradykinin and subsequent activation of bradykinin type 2 receptors (B2). Since COX activity plays a pivotal role in B2 signaling, the aim of this study was to determine which prostaglandins are the key mediators and which COX, COX-1 or COX-2, is predominantly involved. METHODS: We used Miles assays to assess the effects of inhibitors of COX, 5-lipoxygenase, epoxyeicosatrienoic acid generation, cytosolic phospholipase A2α and a variety of prostaglandin receptor antagonists on bradykinin-induced dermal extravasation in C57BL/6 and COX-1-deficient mice (COX-1-/-). In addition, the prostacyclin metabolite 6-keto-PGF1α was quantified by ELISA in subcutaneous tissue from C57BL/6 and human dermal microvascular endothelial cells. In the latter, 6-keto-PGF1α was also quantified and identified by LC-MS/MS. RESULTS: Unspecific COX inhibition by ibuprofen and diclofenac significantly reduced B2-mediated dermal extravasation in C57BL/6 but not COX-1-/-. Likewise, inhibition of cytosolic phospholipase A2α showed similar effects. Furthermore, extravasation in COX-1-/- was generally lower than in C57BL/6. Of the prostaglandin antagonists used, only the prostacyclin receptor antagonist RO1138452 showed a significant reduction of dermal extravasation. Moreover, 6-keto-PGF1α concentrations were increased after bradykinin treatment in subcutaneous tissue from C57BL/6 as well as in human dermal microvascular endothelial cells and this increase was abolished by diclofenac. CONCLUSION: Our findings suggest that COX-1-dependent prostacyclin production is critically involved in dermal extravasation after activation of B2 in small dermal blood vessels. Targeting prostacyclin production and/or signaling appears to be a suitable option for acute treatment of non-allergic angioedema.

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

BACKGROUND: 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. METHODS: 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 healthy volunteers received i.d. bradykinin injections into the ventral forearm before and after oral treatment with the COX inhibitor ibuprofen (600 mg). The primary endpoint of ABRASE was the mean time to complete resolution of wheals (TTCR) and the secondary endpoint was the change of maximal wheal size. RESULTS: Neither NOS inhibitors nor eNOS deficiency altered bradykinin-induced extravasation. In striking contrast, the COX inhibitors ibuprofen, diclofenac, SC560 and celecoxib significantly diminished this extravasation when given before injection. As for diclofenac, a similar but significantly lower effect was observed when given after i.d. injection of bradykinin. Similar results were obtained when bradykinin was replaced by labradimil. In volunteers, ibuprofen significantly reduced TTCR (P < 0.001) and maximal wheal size (P = 0.0044). CONCLUSION: These data suggest that COX activity contributes to bradykinin-induced dermal extravasation in mice and humans. In addition, our findings may open new treatment options and point to a potential activity of drugs interfering with the release of the COX substrate arachidonic acid, e.g. glucocorticoids.