BACKGROUND Neuromuscular blocking agents (NMBAs) can cause both IgE-dependent and independent anaphylactic reactions, with activation of the mast cell receptor MRGPRX2 being important to the latter. Sugammadex, a reversal agent for certain aminosteroid NMBAs, has been proposed as an antidote for these anaphylactic events with conflicting outcomes. OBJECTIVE We further characterise the involvement of MRGPRX2 in NMBA-induced mast cell activation and determine how this is influenced by sugammadex. We then apply these in vitro results to infer the possible utility of sugammadex in the acute management of non-IgE dependent anaphylaxis. METHODS The LAD2 human mast cell line and a MRGPRX2 knock-down derivative were used to validate the involvement of MRGPRX2 and to test the effect of sugammadex on mast cell activation by NMBAs and other MRGPRX2 agonists. RESULTS All MRGPRX2 agonists tested were shown to induce MRGPRX2-dependent LAD2 mast cell calcium mobilization and cytokine release and all, apart from rocuronium, induced degranulation. Co-treatment of mast cells with sugammadex and some MRGPRX2 agonists significantly reduced cell activation, but if sugammadex was administered a few minutes following stimulation, degranulation was not attenuated. However, addition of sugammadex up to 180 minutes following LAD2 MRGPRX2 stimulation, significantly reduced CCL2 mRNA and protein induction. CONCLUSIONS AND CLINICAL RELEVANCE We show that sugammadex, known to reverse muscle blockade by certain NMBAs, is also able to reduce MRGPRX2 activation by NMBAs and other, but not all, MRGPRX2 agonists. As sugammadex was ineffective in attenuating mast cell degranulation when added rapidly post MRGPRX2 activation, this suggests against the agent having efficacy in controlling acute symptoms of anaphylaxis to NMBAs caused by MRGPRX2 activation. Interestingly however, sugammadex did impair MRGPRX2-induced CCL2 release, suggesting that it may have some benefit in perhaps dampening less well-defined adverse effects of MRGPRX2-dependent anaphylaxis associated with the more slowly elaborated mast cell mediators.

中文翻译：

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神经肌肉阻滞剂和其他激动剂激活肥大细胞中的 MRGPRX2：舒更葡糖的调节

背景技术神经肌肉阻滞剂(NMBA)可引起IgE依赖性和独立的过敏反应，肥大细胞受体MRGPRX2的激活对后者很重要。Sugammadex 是某些氨基类固醇 NMBA 的逆转剂，已被提议作为这些结果相互矛盾的过敏事件的解毒剂。目的 我们进一步描述了 MRGPRX2 在 NMBA 诱导的肥大细胞活化中的作用，并确定了舒更葡糖如何影响这一过程。然后，我们应用这些体外结果来推断 sugammadex 在非 IgE 依赖性过敏反应的急性管理中的可能效用。方法 LAD2 人肥大细胞系和 MRGPRX2 敲低衍生物用于验证 MRGPRX2 的参与，并测试舒更葡糖对 NMBA 和其他 MRGPRX2 激动剂激活肥大细胞的影响。结果显示，所有测试的 MRGPRX2 激动剂均诱导 MRGPRX2 依赖性 LAD2 肥大细胞钙动员和细胞因子释放，除罗库溴铵外，所有药物均诱导脱粒。用舒更葡糖和一些 MRGPRX2 激动剂共同处理肥大细胞显着降低了细胞活化，但如果在刺激后几分钟给予舒更葡糖，脱颗粒没有减弱。然而，在 LAD2 MRGPRX2 刺激后 180 分钟内添加舒更葡糖显着降低了 CCL2 mRNA 和蛋白质的诱导。结论和临床相关性 我们表明，已知可逆转某些 NMBA 的肌肉阻滞作用的舒更葡糖也能够减少 NMBA 和其他（但不是全部）MRGPRX2 激动剂对 MRGPRX2 的激活。由于在 MRGPRX2 激活后快速添加 sugammadex 在减弱肥大细胞脱粒方面无效，这表明该药剂在控制由 MRGPRX2 激活引起的 NMBA 过敏反应的急性症状方面具有效力。然而，有趣的是，舒更葡糖确实削弱了 MRGPRX2 诱导的 CCL2 释放，这表明它可能在抑制与更缓慢阐述的肥大细胞介质相关的 MRGPRX2 依赖性过敏反应的不太明确的副作用方面可能具有一些益处。