Involvement of p38 MAPK/cPLA2 and arachidonic acid metabolic pathway in Shengmai injection-induced pseudo-allergic reactions

Shengmai injection (SMI) is a well-known Chinese tonifying medicine. Intravenous SMI was prepared using purified ginseng, Ophiopogonis radix, and Schisandra chinensis. SMI is effective for the treatment of heart failure, tumors, pulmonary heart disease, etc., and can improve the curative effect of conventional treatment when used as an adjuvant with Western medicine (Liao et al., 2020; Zhang et al., 2010; Yan et al., 2014; Lei and Duan, 2020). In addition, SMI showed beneficial effect on the treatment of corona virus disease 2019 (COVID-19) and was recommended to cure critically ill patients (Zhuang et al., 2020). Besides, SMI has been included in several guidelines for various infectious diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (Zhong, 2003; National Health and Family Planning Commission of People's Republic of China., 2015).

However, adverse drug reactions (ADRs) have been reported in approximately 8% of the patients treated with SMI. These ADRs involve several organs and tissues, including the skin and respiratory system, with symptoms, such as rash, itching, chest tightness, dyspnea, and anaphylaxis (Zhang et al., 2010). ADRs rapidly occur after SMI administration and appear to be immediate hypersensitive reactions. Therefore, they are often reported as “type I allergic reactions” in clinical practice and are considered as IgE-mediated immune reactions.

Theoretically, for IgE-mediated drug allergic reactions, when patients are treated with drugs for the first time, they are only sensitized, and no symptoms appear. Allergic reactions can be observed when sensitized individuals are re-exposed to the same drugs (Descotes, 2005). Pseudo-allergic reactions (PARs) may exhibit symptoms similar to those of immediate allergic reactions but lack immunological specificity. In these reactions, non-immune mechanisms trigger the release of histamine and other inflammatory mediators by effector cells (such as mast cells and basophils). PARs can occur during the first medication and show a dose-response relationship (Pichler and Hausmann, 2016). Results from various medical centers indicate that most SMI-mediated hypersensitivity reactions occur during the first exposure, with >50% of the cases occurring within 30 min of SMI administration (Chen et al., 2011). Hence, most SMI hypersensitivity reactions are postulated to be PARs.

Mechanistically, PARs are mostly triggered by the direct degranulation of mast cells, activation of the complement system, and stimulation of inflammatory reaction-related enzymes and/or vascular permeability-related pathways (Macy, E, & Ensina, L.F, 2019). A major inflammatory pathway involved is the arachidonic acid (AA) pathway, which produces many AA metabolites (AAMs) and causes various inflammatory diseases, such as allergies and asthma (Serrano-Mollar, A, & Closa, D 2005). In this pathway, esterified AA (on the inner surface of the cell membrane) is hydrolyzed to its free form by phospholipase A2 (PLA2) and then metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) into a series of bioactive mediators, including prostaglandins (PGs), leukotrienes (LTs), and hydroxy-eicosatetraenoic acids (HETEs) (Wang et al., 2021). COX-2 catalyzes the generation of PGs (e.g., PGD2, PGE2, PGF2, PGI2, and thromboxane A2) from AA, which are the major sources of PGs in inflammatory diseases (Claar et al., 2015). The enzyme 5-LOX produces LTs from AA by interacting with the 5-LOX-activating protein (FLAP) to catalyze the formation of leukotriene A4 (LTA4), which can then be converted to LTB4 or cysteinyl LTs (LTC4, LTD4, and LTE4). These LTs can facilitate smooth muscle contraction (especially bronchoconstriction), increase vascular permeability, and promote leukocyte migration to inflamed areas (Abueid et al., 2017). The p38 MAPK/cPLA2 signaling pathway plays a key role in inflammation (Lin et al., 1993). When p38 MAPK is phosphorylated, it can directly activate cytosolic cPLA2 and lead to augmented production of free AA, which is then converted into bioactive mediators, such as PGs, LTs, and HETEs to accelerate inflammatory responses and tissue damage (Henderson et al., 2007).

Many symptoms exhibited in PARs, such as skin redness, itching, chest tightness, wheezing, and dyspnea, may be associated with increased vascular leakage. Therefore, a model that easily assess vascular permeability could be used to evaluate PARs. In previous studies, we have established a mouse model suitable to distinguish PARs and immediate allergic reactions, as well as estimate the severity of the reactions based on evaluating vascular permeability. The test results obtained from this model have been verified in consistent with anti-drug specific IgE, passive cutaneous anaphylaxis test, and clinical reports (Liang et al., 2012; Li et al., 2011; Yi et al., 2022; Han et al., 2016, 2018). In the present study, we used this model to explore the underlying mechanisms involved in SMI-induced ADRs.

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