Wang Dunfang, Han Jiayin, Pan Chen, Li Chunying, Zhao Yong, Liu Suyan, Zhang Yushi, Tian Jingzhuo, Yi Yan, Zhu Jingjing, Liu Chenyue, Wang Yuan, Xian Zhong, Meng Jing, Qin Shasha, Tang Xuan, Wang Fang, Liang Aihua
Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
National Engineering Laboratory for Quality Control Technology of Chinese Herbal Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Front Pharmacol. 2022 Aug 22;13:874486. doi: 10.3389/fphar.2022.874486. eCollection 2022.
Metabolites/impurities (MIs) of penicillin are normally considered to be the main substances inducing immediate hypersensitivity reactions in penicillin treatment. Our previous research found that penicillin can cause non-allergic hypersensitivity reactions (NAHRs) by directly triggering vascular hyperpermeability and exudative inflammation. However, the chief culprits and underlying mechanisms involved in penicillin-induced NAHRs have not yet been fully elucidated. In this study, we used a combination of approaches including a mouse non-allergic hypersensitivity reaction model, UPLC-MS/MS analyses of arachidonic acid metabolites (AAMs), immunoblotting technique, and molecular docking, etc to investigate the culprits involved in penicillin-induced hypersensitivity reactions. We found penilloic acid, one of the main MIs of penicillin, could trigger NAHRs via inducing increased vascular permeability, while the other MIs did no exhibit similar effect. Penilloic acid-induced reactions were not IgE-dependent. Significantly increased arachidonic acids and cascade metabolites in lungs, and activation of RhoA/ROCK signaling pathway in the ears and lungs of mice were noticed after once administration of penilloic acid. This study revealed that penilloic acid was the chief culprit involved in penicillin-induced immediate NAHRs in mice, which mainly associated with direct stimulation of vascular hyperpermeability and exudative inflammation. The activations of AAMs and RhoA/ROCK signaling pathway played important roles in these reactions.
青霉素的代谢产物/杂质（MIs）通常被认为是青霉素治疗中引起速发型超敏反应的主要物质。我们之前的研究发现，青霉素可通过直接引发血管通透性增加和渗出性炎症而导致非过敏性超敏反应（NAHRs）。然而，青霉素诱导的NAHRs所涉及的主要元凶及潜在机制尚未完全阐明。在本研究中，我们采用了包括小鼠非过敏性超敏反应模型、花生四烯酸代谢产物（AAMs）的超高效液相色谱-串联质谱分析、免疫印迹技术和分子对接等多种方法，来研究青霉素诱导的超敏反应所涉及的元凶。我们发现，青霉素的主要MIs之一青霉噻唑酸可通过诱导血管通透性增加而引发NAHRs，而其他MIs则未表现出类似作用。青霉噻唑酸诱导的反应不依赖于IgE。单次给予青霉噻唑酸后，小鼠肺中花生四烯酸及其级联代谢产物显著增加，且耳和肺中的RhoA/ROCK信号通路被激活。本研究表明，青霉噻唑酸是小鼠青霉素诱导的速发型NAHRs的主要元凶，这主要与直接刺激血管通透性增加和渗出性炎症有关。AAMs和RhoA/ROCK信号通路的激活在这些反应中起重要作用。
