Institute of Pharmacology andClinical Pharmacology, University Hospital, Heinrich Heine University, Düsseldorf, Germany.
Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, Germany.
Biomed Pharmacother. 2020 Mar;123:109797. doi: 10.1016/j.biopha.2019.109797. Epub 2019 Dec 23.
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 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.
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).
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.
非过敏性血管性水肿主要由血浆中缓激肽水平升高和缓激肽受体 2（B2）过度激活引起，但具体的下游信号通路仍不清楚。本研究旨在鉴定缓激肽诱导皮肤外渗涉及的信号转导事件。
通过在内皮型一氧化氮合酶（eNOS）缺陷小鼠和预先给予载体、一氧化氮合酶或环氧化酶（COX）抑制剂的 C57BL/6J 小鼠皮内注射缓激肽或 B2 激动剂 labradimil，定量测定皮肤外渗。在多中心临床研究 ABRASE 中，38 名健康志愿者在前臂腹侧皮内注射缓激肽，然后口服 COX 抑制剂布洛芬（600mg）。ABRASE 的主要终点是完全消退风团的平均时间（TTCR），次要终点是最大风团大小的变化。
NOS 抑制剂和 eNOS 缺陷均未改变缓激肽诱导的外渗。相比之下，COX 抑制剂布洛芬、双氯芬酸、SC560 和塞来昔布在注射前给予时明显减少了这种外渗。对于双氯芬酸，当在皮内注射缓激肽后给予时，也观察到类似但显著较低的作用。当用 labradimil 替代缓激肽时，也得到了类似的结果。在志愿者中，布洛芬显著降低 TTCR（P<0.001）和最大风团大小（P=0.0044）。
这些数据表明 COX 活性有助于小鼠和人类中缓激肽诱导的皮肤外渗。此外，我们的发现可能为治疗提供新的选择，并表明干扰 COX 底物花生四烯酸释放的药物（例如糖皮质激素）可能具有潜在的活性。
