Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, 151 North Ma Lian Wa Road, Haidian District, Beijing, People's Republic of China.
Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, People's Republic of China.
Sci Rep. 2020 Aug 25;10(1):14160. doi: 10.1038/s41598-020-71083-x.
Immediate hypersensitivity reaction (IHR) can be divided into allergic- and non-allergic-mediated, while "anaphylaxis" is reserved for severe IHR. Clinically, true penicillin allergy is rare and most reported penicillin allergy is "spurious". Penicillin-initiated anaphylaxis is possible to occur in skin test- and specific IgE-negative patients. The contact system is a plasma protease cascade initiated by activation of factor XII (FXII). Many agents with negative ion surface can activate FXII to drive contact system. Our data showed that penicillin significantly induced hypothermia in propranolol- or pertussis toxin-pretreated mice. It also caused a rapid and reversible drop in rat blood pressure, which did not overlap with IgE-mediated hypotension. These effects could be countered by a bradykinin-B2 receptor antagonist icatibant, and consistently, penicillin indeed increased rat plasma bradykinin. Moreover, penicillin not only directly activated contact system FXII-dependently, but also promoted bradykinin release in plasma incubated-human umbilical vein endothelial cells. In fact, besides penicillin, other beta-lactams also activated the contact system in vitro. Since the autoactivation of FXII can be affected by multiple-factors, plasma from different healthy individuals showed vastly different amidolytic activity in response to penicillin, suggesting the necessity of determining the potency of penicillin to induce individual plasma FXII activation. These results clarify that penicillin-initiated non-allergic anaphylaxis is attributed to contact system activation, which might bring more effective diagnosis options for predicting penicillin-induced fatal risk and avoiding costly and inappropriate treatment clinically.
即刻超敏反应 (IHR) 可分为过敏和非过敏介导，而“过敏反应”则保留给严重的 IHR。临床上，真正的青霉素过敏很少见，大多数报告的青霉素过敏是“假性”的。皮试和特异性 IgE 阴性患者也可能发生青霉素引发的过敏反应。接触系统是一种由因子 XII (FXII) 激活引发的血浆蛋白酶级联反应。许多带有负离子表面的物质可以激活 FXII 来驱动接触系统。我们的数据表明，青霉素可显著诱导普萘洛尔或百日咳毒素预处理的小鼠体温降低。它还导致大鼠血压迅速而可逆地下降，与 IgE 介导的低血压不重叠。这些作用可被缓激肽 B2 受体拮抗剂 icatibant 拮抗，并且一致地，青霉素确实增加了大鼠血浆中的缓激肽。此外，青霉素不仅直接依赖 FXII 激活接触系统，还促进了人脐静脉内皮细胞孵育的血浆中缓激肽的释放。事实上，除了青霉素外，其他β-内酰胺类抗生素也在体外激活了接触系统。由于 FXII 的自身激活会受到多种因素的影响，来自不同健康个体的血浆对青霉素的酰胺酶活性有很大差异，这表明有必要确定青霉素诱导个体血浆 FXII 激活的效力。这些结果阐明了青霉素引发的非过敏型过敏反应归因于接触系统的激活，这可能为预测青霉素诱导的致命风险并在临床上避免昂贵和不适当的治疗提供更有效的诊断选择。
