目前，不良反应限制了中药注射剂的发展，其中严重过敏性休克是严重不良反应之一，这对中药注射剂提出了重大挑战。在使用TCMI之前如果存在异常炎症介质，很可能会导致严重的过敏样反应。不仅如此，缺乏临床相关的安全性评价阻碍了中药注射液的广泛使用，迫切需要研究揭示中药注射液引起过敏性休克的机制。利用豚鼠模型，诱导炎症，从而加重TCMI引起的过敏样反应。以豚鼠为模型，检查LPS给药的剂量和持续时间以及化合物48/80(C48/80)的不同剂量。采用双黄连（SHLI）和清开灵（QKLI）注射液这两种代表性中药注射液进行验证。分析血浆生化指标组胺、5-羟色胺、肿瘤坏死因子-α、白细胞介素6、免疫球蛋白E、C5a、类胰蛋白酶、血小板活化因子以及肺部病理特征。此外，血浆代谢组学被用来揭示炎症与 TCMI 共存时体内代谢途径的变化。此外，还进行了蛋白质印迹分析以评估关键信号通路的表达。用 2 mg/kg LPS 刺激 12 小时可在豚鼠模型中诱导炎症反应。 C48/80 (3.0 mg/kg) 与 LPS 结合导致血浆中过敏反应相关指标增加。高剂量的SHLI和QKLI加重了LPS引起的炎症引起的血浆指数和肺组织学损伤。 SHLI 和 QKLI 处理的豚鼠组在 LPS 刺激后分别有 36 种和 63 种差异代谢物发生显着改变。相关的代谢途径包括癌症中的中心碳代谢、三羧酸循环、乙醛酸和二羧酸代谢。 LPS刺激后体内TCMI可能显着影响p38/ERK/NF-κB信号通路。LPS诱导的炎症加重了SHLI和QKLI引起的类过敏反应，且与剂量相关。 LPS 存在后，TCMI 的施用会通过过度激活 p38/ERK/NF-κB 信号通路来干扰免疫反应。这种激活导致炎症因子和过敏样介质的过度释放。这些结果为减轻与 TCMI 相关的临床不良反应提供了新方向。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Currently, adverse reactions limit the development of traditional Chinese medicine injections (TCMI), and severe anaphylactoid shock is one of the serious adverse reactions, which presents a significant challenge. The presence of abnormal inflammatory mediators before the administration of TCMI will most likely result in severe anaphylactoid reactions. Not only that, the lack of clinically relevant safety evaluations impedes the widespread use of TCMI, and there is an urgent need for studies to reveal the mechanisms of anaphylactoid shock caused by TCMI.To investigate the effects and underlying mechanisms of lipopolysaccharide (LPS)-induced inflammation, which aggravates anaphylactoid reactions caused by TCMI, utilizing a guinea pig model.The dose and duration of LPS administration and different doses of compound 48/80 (C48/80) were examined by using guinea pigs as a model. Shuanghuanglian (SHLI) and Qingkailing (QKLI) injections, these two representative TCMI, were used for validation. The plasma biochemical indices, including histamine, 5-hydroxytryptamine, tumor necrosis factor-α, interleukin 6, immunoglobulin E, C5a, tryptase, and platelet activating factor, as well as the pathological characteristics of the lung, were analyzed. Futhermore, plasma metabolomics was employed to reveal changes in metabolic pathways in vivo when inflammation co-exists with TCMI. In addition, Western blot analysis was conducted to assess the expression of critical signaling pathways.Stimulation with 2 mg/kg of LPS for 12 h induced inflammatory responses in the guinea pig model. C48/80 (3.0 mg/kg) in combination with LPS resulted in an increase in anaphylactoid-related indicators in the plasma. High doses of SHLI and QKLI aggravated plasma indices and lung histological injury caused by LPS-induced inflammation. A total of 36 and 63 differential metabolites were significantly altered after LPS stimulation in the SHLI-and QKLI-treated guinea pig groups, respectively. The associated metabolic pathways include central carbon metabolism in cancer, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism. The p38/ERK/NF-κB signal pathway may be significantly affected by TCMI in vivo after LPS stimulation.LPS-induced inflammation aggravated anaphylactoid reactions caused by SHLI and QKLI, with a correlation to dosage. After the presence of LPS, the administration of TCMI interferes with the immune response by over-activating the p38/ERK/NF-κB signaling pathway. This activation leads to an excessive release of inflammatory factors and anaphylactoid mediators. These results present a new direction for mitigating adverse clinical reactions associated with TCMI.Copyright © 2024 Elsevier B.V. All rights reserved.