College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing 210023, China.
J Ethnopharmacol. 2025 Jan 30;337(Pt 3):118946. doi: 10.1016/j.jep.2024.118946. Epub 2024 Oct 16.
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.
目前，不良反应限制了中药注射液（TCMI）的发展，严重的类过敏休克是其中一种严重的不良反应，这是一个重大的挑战。TCMI 给药前异常炎症介质的存在很可能导致严重的类过敏反应。不仅如此，缺乏临床相关的安全性评估阻碍了 TCMI 的广泛应用，因此迫切需要研究揭示 TCMI 引起的类过敏休克的机制。
利用豚鼠模型研究脂多糖（LPS）诱导的炎症加重 TCMI 引起的类过敏反应的作用及机制。
以豚鼠为模型，考察 LPS 给药剂量和时间以及不同剂量的化合物 48/80（C48/80）的作用。验证了两种代表性的 TCMI，双黄连（SHLI）和清开灵（QKLI）注射液。分析了包括组胺、5-羟色胺、肿瘤坏死因子-α、白细胞介素 6、免疫球蛋白 E、C5a、胰蛋白酶和血小板激活因子在内的血浆生化指标以及肺的病理特征。此外，还进行了血浆代谢组学分析，以揭示炎症共存时体内代谢途径的变化。另外，还进行了 Western blot 分析以评估关键信号通路的表达。
LPS 刺激 2mg/kg 12h 可诱导豚鼠模型炎症反应。C48/80（3.0mg/kg）与 LPS 联合使用可导致 LPS 诱导的炎症引起的类过敏相关指标增加。SHLI 和 QKLI 的高剂量加重了 LPS 诱导的炎症引起的血浆指标和肺组织学损伤。LPS 刺激后，SHLI 和 QKLI 处理的豚鼠组分别有 36 和 63 个差异代谢物显著改变。相关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 可能会显著影响 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，且与剂量有关。在 LPS 存在的情况下，TCMI 的给药通过过度激活 p38/ERK/NF-κB 信号通路干扰免疫反应。这种激活导致炎症因子和类过敏介质的过度释放。这些结果为减轻 TCMI 相关临床不良反应提供了新的方向。
