首页|Contribution of cyclooxygenase-1-dependent prostacyclin synthesis to bradykinin-induced dermal extravasation
Contribution of cyclooxygenase-1-dependent prostacyclin synthesis to bradykinin-induced dermal extravasation
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NSTL
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 A_2α 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-PGF_1α was quantified by ELISA in subcutaneous tissue from C57BL/6 and human dermal microvascular endothelial cells。 In the latter， 6-keto-PGF_1α 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 A_2α 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-PGF_1α 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。
NSTL
