Compound Kushen Injection Induces Immediate Hypersensitivity Reaction Through Promoting the Production of Platelet-Activating Factor via de Novo Pathway.

Yuan Gao,Fang Liu,Yuan Kang,Wenjie Qin,Xiuwei Yang,Runlan Cai,Yun Qi,Lina Hai

doi:10.3389/fphar.2021.768643

Abstract

Compound Kushen Injection (CKI) is a bis-herbal formulation extracted from Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Heterosmilacis Yunnanensis). Clinically, it is used as the adjuvant treatment of cancer. However, with the increased application, the cases of immediate hypersensitivity reactions (IHRs) also gradually rise. In this study, we investigated the underlying mechanism(s) and active constituent(s) for CKI-induced IHRs in experimental models. The obtained results showed that CKI did not elevate serum total IgE (tIgE) and mouse mast cell protease 1 (MMCP1) after consecutive immunization for 5 weeks, but could induce Evans blue extravasation (local) and cause obvious hypothermia (systemic) after a single injection. Further study showed that alkaloids in Kushen, especially matrine, were responsible for CKI-induced IHRs. Mechanism study showed that various platelet-activating factor (PAF) receptor antagonists could significantly counter CKI-induced IHRs locally or systemically. In cell system, CKI was able to promote PAF production in a non-cell-selective manner. In cell lysate, the effect of CKI on PAF production became stronger and could be abolished by blocking de novo pathway. In conclusion, our study identifies, for the first time, that CKI is a PAF inducer. It causes non-immunologic IHRs, rather than IgE-dependent IHRs, by promoting PAF production through de novo pathway. Alkaloids in Kushen, especially matrine, are the prime culprits for IHRs. Our findings may provide a potential approach for preventing and treating CKI-induced IHRs.

Highlights

Compound Kushen Injection (CKI), called “fufangkushen injection”, is a Chinese patent medicine extracted from two herbs: Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Heterosmilacis Yunnanensis)
If CKI-induced immediate hypersensitivity reactions (IHRs) is through IgE/FcεRI signaling, serum total IgE (tIgE) and mouse mast cell protease 1 (MMCP1) (another specific marker for IgE-mediated mast cell activation (Khodoun et al, 2011)) levels should be significantly increased
The positive control Shrimp tropomyosin (ST) markedly elevated serum tIgE and MMCP1 levels after continuous intraperitoneal immunization, while CKI could not increase these two markers (Figure 2), demonstrating that CKI-induced IHR was independent of IgE/FcεRI-mediated signaling

Summary

Introduction

Compound Kushen Injection (CKI), called “fufangkushen injection”, is a Chinese patent medicine extracted from two herbs: Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Heterosmilacis Yunnanensis). It was approved by State Food and Drug Administration of China for the adjuvant treatment of cancer more than 20 years ago (Guo et al, 2015). Since IHRs may occur by immune-mediated or nonimmune-mediated mechanisms, they are classified as immunologic IHRs (IN-IHRs) or nonimmunologic IHRs (NIN-IHRs) Regarding the former, most drugs act as haptens or prohaptens to become immunogenic inducing IN-IHRs. IgG-mediated IHRs were reported in animal models (Muñoz-Cano et al, 2016), INIHRs are almost always mediated by IgE in humans (JimenezRodriguez et al, 2018). NIN-IHRs cannot be distinguishable from IgE-mediated IHRs clinically (Aun et al, 2017) and have been described, such as direct degranulation of mast cells/ basophils (Johansson et al, 2004), cytokine-release reactions (Nakamura and Murata, 2018), complement activation (Gao et al, 2018; Gao et al, 2020a), or contact system activation (Gao et al, 2020b), etc

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