sinomenine and Anaphylaxis

Zhengqing Fengtongning (ZQFTN), the pharmaceutical preparation of sinomenine (SIN) derived from the medicinal plant Sinmenium acutum, is well-known in China as an effective treatment for rheumatoid arthritis (RA). However, its histamine-release anaphylactoid reactions (HRARs) occur often in some patients. Therefore, it is desirable to establish effective clinical protocols to manage such HRARs. In the study, rat models with systemic HRARs and local HRARs of the skin were established. The level of vascular permeability and mast cell numbers was determined by quantitative analysis using Evans blue dye and histological assays. The levels of histamine, leukotriene B4 (LTB4) and IL-33 in plasma were detected by UHPLC-SPE-MS, ELISA and immunohistochemistry assays, respectively. The results demonstrated that SIN significantly induced both systemic and local HRARs in rats, showing significant decrease of body temperature, increases in vascular permeability in skin, injury of lung tissues and mast cell infiltration and IL-33 expression in skin and lung tissues. Mechanistic study showed that tranilast could prevent SIN-triggered HRARs via inhibition of H1 receptor gene expression and NF-κB signaling. Our findings provide evidence that mast cell membrane stabilizers and H1 receptor blockers effectively prevent SIN-induced HRARs, and cromolyn, cetirizine and tranilast can be used in the clinic for the management of HRARs induced by ZQFTN.

Topics: Acute Lung Injury; Anaphylaxis; Animals; Anti-Allergic Agents; Cetirizine; Cromolyn Sodium; Female; Histamine; Histamine H1 Antagonists; Histamine Release; Interleukin-33; Leukotriene B4; Lung; Mast Cells; Morphinans; NF-kappa B; ortho-Aminobenzoates; Rats, Sprague-Dawley; Receptors, Histamine H1; Signal Transduction; Skin

Mast cells are unique immunocytes that function as sentinel cells in host defense reactions such as immediate hypersensitivity responses and anaphylactic responses. The mast cell specific receptor MRGPRX2 (Mas-related G protein-coupled receptor X2) triggers mast cell degranulation-a key process in anaphylactic reactions. We sought to better understand anaphylactic reaction induced by sinomenine hydrochloride (SH). MRGPRX2-related pseudo-allergic reactions induced by SH were investigated using the hindpaw swelling and extravasation assay in vivo and mast cell degranulation assays in vitro. MrgprB2 knockout mice exhibit a reduced SH-induced inflammation effect. Furthermore, MRGPRX2 (the orthologous gene of MrgprB2) related human mast cells are activated by SH in a dose-dependent manner; however, MRGPRX2 knockdown mast cells showed reduced degranulation. The results showed a kind of mechanism that SH-induced anaphylactoid reactions were mediated by MRGPRX2 via activating PLC molecular signaling pathways to provoke mast cells Ca

Topics: Anaphylaxis; Animals; Antirheumatic Agents; Calcium Signaling; Cell Line; Cells, Cultured; Gene Expression Regulation; Humans; Mast Cells; Mice; Mice, Knockout; Morphinans; Nerve Tissue Proteins; Peritoneum; Receptors, G-Protein-Coupled; Receptors, Neuropeptide

Mast cells are vital mediators of drug allergy and, therefore, studying the relationship between drug allergy and mast cells is essential. Sinomenine is the principal active component of Sinomenium acutum, which has anti-inflammatory and anti-immune effects, and is used to treat various rheumatoid diseases. However, allergic responses to sinomenine are frequently reported. Therefore, this study assessed the effects of sinomenine on mast cell activation to characterize its allergic effects and the underlying mechanisms. Enzyme-linked immunosorbent assay (ELISA), western blot analyses, and degranulation assays were performed to measure pro-inflammatory and allergic mediators in P815 cells. The allergenic effects of sinomenine were also determined in mice by using active general anaphylaxis (ASA). The results indicated that sinomenine induced inositol-1,4,5-trisphosphate (IP

Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Calcium; Cell Degranulation; Cell Line, Tumor; Drug Hypersensitivity; Inflammation; Inositol 1,4,5-Trisphosphate Receptors; Interleukin-6; Male; Mast Cells; Mice; Mice, Inbred BALB C; Morphinans; Phospholipase C gamma; Phosphorylation; Signal Transduction; src-Family Kinases; Up-Regulation

Sinomenine (SIN), an alkaloid derived from the Chinese medicinal plant Sinomenium acutum, is the major component of Zhengqing Fongtong Ning (ZQFTN), a pharmaceutical drug produced by Hunan Zhengqing Pharmaceutical Co. Ltd. in China for the treatment of rheumatoid arthritis and other autoimmune diseases. Some clinic reports indicate that ZQFTN may induce an anaphylactic reaction via potentiating the degranulation of immune cells. In the current study, we aimed to examine whether SIN is capable of inducing the degranulation of basophilic leukemia 2H3 (RBL-2H3) cells to elucidate how the anaphylactic reaction occurs. The results revealed that SIN could up-regulate β-hexosaminidase levels in RBL-2H3 cells without significant cytotoxicity, suggesting that SIN could induce the degranulation of RBL-2H3 cells. Furthermore, SIN increased the release of prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2) in RBL-2H3 cells via promoting the expression of phosphorylated-extracellular signal-regulated kinase (P-ERK), the cleavage of Annexin A1 (ANXA1), and phosphorylated-cytosolic phospholipase A2 (P-cPLA2), as well as cyclooxygenase-2 (COX-2). The ERK inhibitor, PD98059, significantly attenuated the up-regulatory effect of SIN on cPLA2 phosphorylation. Interestingly, SIN did not significantly increase Ca(2+) influx in the cells. These findings not only explored the anaphylactic reaction and underlying mechanism of ZQFTN in RBL-2H3 cells, but may promote the development of relevant strategies for overcoming the adverse effects of the drug.

Topics: Anaphylaxis; Animals; Annexin A1; Arthritis, Rheumatoid; Basophils; Calcium; Cell Degranulation; Cell Line; Drug Hypersensitivity; Humans; MAP Kinase Signaling System; Morphinans; Phospholipases A2; Phosphorylation; Rats; Sinomenium