Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Front Immunol. 2023 Mar 21;14:1135701. doi: 10.3389/fimmu.2023.1135701. eCollection 2023.
The mechanism of the immediate adverse drug reactions (ADRs) induced by ShenMai injection (SMI) has not been completely elucidated. Within 30 minutes, the ears and lungs of mice injected with SMI for the first time showed edema and exudation reactions. These reactions were different from the IV hypersensitivity. The theory of pharmacological interaction with immune receptor (p-i) offered a new insight into the mechanisms of immediate ADRs induced by SMI.
In this study, we determined that the ADRs were mediated by thymus-derived T cells through the different reactions of BALB/c mice (thymus-derived T cell normal) and BALB/c nude mice (thymus-derived T cell deficient) after injecting SMI. The flow cytometric analysis, cytokine bead array (CBA) assay and untargeted metabolomics were used to explain the mechanisms of the immediate ADRs. Moreover, the activation of the RhoA/ROCK signaling pathway was detected by western blot analysis.
In BALB/c mice, the vascular leakage and histopathology results showed the occurrence of the immediate ADRs induced by SMI. The flow cytometric analysis revealed that CD4 T cell subsets (Th1/Th2, Th17/Treg) were imbalanced. And the levels of cytokines such as IL-2, IL-4, IL12P70 and INF-γ increased significantly. However, in BALB/c nude mice, all the indicators mentioned above have not changed significantly. The metabolic profile of both BALB/c mice and BALB/c nude mice was significantly changed after injecting SMI, and the notable increase in lysolecithin level might have a greater association with the immediate ADRs induced by SMI. The Spearman correlation analysis revealed that LysoPC (18:3(6Z,9Z,12Z)/0:0) showed a significant positive correlation with cytokines. After injecting SMI, the levels of RhoA/ROCK signaling pathway-related protein increased significantly in BALB/c mice. Protein-protein interaction (PPI) showed that the increased lysolecithin levels might be related to the activation of the RhoA/ROCK signaling pathway.
Together, the results of our study revealed that the immediate ADRs induced by SMI were mediated by thymus-derived T cells, and elucidated the mechanisms of such ADRs. This study provided new insights into the underlying mechanism of immediate ADRs induced by SMI.
参麦注射液（SMI）引起的即时药物不良反应（ADR）的机制尚未完全阐明。在首次注射 SMI 的 30 分钟内，小鼠的耳朵和肺部出现水肿和渗出反应。这些反应与 IV 过敏反应不同。药理学与免疫受体相互作用理论（p-i）为 SMI 引起的即时 ADR 机制提供了新的见解。
本研究通过注射 SMI 后 BALB/c 小鼠（胸腺来源 T 细胞正常）和 BALB/c 裸鼠（胸腺来源 T 细胞缺乏）的不同反应，确定 ADR 是由胸腺来源的 T 细胞介导的。采用流式细胞术分析、细胞因子珠阵列（CBA）检测和非靶向代谢组学方法来解释即时 ADR 的机制。此外，通过 Western blot 分析检测 RhoA/ROCK 信号通路的激活情况。
在 BALB/c 小鼠中，血管渗漏和组织病理学结果显示 SMI 引起的即时 ADR 发生。流式细胞术分析显示 CD4 T 细胞亚群（Th1/Th2、Th17/Treg）失衡。并且 IL-2、IL-4、IL12P70 和 INF-γ 等细胞因子水平显著升高。然而，在 BALB/c 裸鼠中，上述所有指标均无明显变化。注射 SMI 后，BALB/c 小鼠和 BALB/c 裸鼠的代谢谱均发生显著变化，溶血磷脂酰胆碱（LysoPC）水平的显著增加可能与 SMI 引起的即时 ADR 有更大的关联。Spearman 相关性分析显示，LysoPC（18:3(6Z,9Z,12Z)/0:0）与细胞因子呈显著正相关。注射 SMI 后，BALB/c 小鼠 RhoA/ROCK 信号通路相关蛋白水平显著升高。蛋白质-蛋白质相互作用（PPI）显示，溶血磷脂酰胆碱水平的升高可能与 RhoA/ROCK 信号通路的激活有关。
综上所述，本研究结果表明，SMI 引起的即时 ADR 是由胸腺来源的 T 细胞介导的，并阐明了这种 ADR 的机制。本研究为 SMI 引起的即时 ADR 机制提供了新的见解。
