Lipopolysaccharide aggravating anaphylactoid reactions caused by traditional Chinese Medicine injections via p38/ERK/NF-κB signaling pathways

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. Thi