ResearchSquare, Posted Date: April 11th, 2024. DOI: https://doi.org/10.21203/rs.3.rs-4186806/v1
Zhen Guo, Cuixiang Zhao, Yanni Fang, Xiuxuan Yue, Qiuxia Wang, Changhua Qu, Jinpeng Cui (Yantaishan Hospital, Weihai Municipal Hospital, China)
Abstract
Introduction: Current clinical asthma therapeutic drugs can produce a series of adverse effects when used for a long period of time or in high doses, so it is urgent to nd new therapeutic strategies.
Solasodine can inhibit ovalbumin (OVA)-induced type II inammation in mice, but the mechanism is still unclear. Mast cell (MCs) degranulation is an important part of allergic reactions, and Src family kinases (SFKs) are involved in the activation of the initiation signal of MC degranulation, and Lyn, Fyn, and Syk among SFKs play important regulatory roles in MC degranulation. Regulation of SFKs can inhibit the MC degranulation process and suppress the occurrence of allergic reactions. Here, we explored the effects of solasodine on OVA-induced asthma in mice and MC-mediated allergic reactions.
Methods: Mouse bone marrow-derived mast cells (BMMCs) cells were added with different concentrations (0, 2, 4, 6, 8,10, 12 and 14 μM) of solasodine to select the appropriate concentration. In transforming growth factor (TGF)-β1 treatment of BMMCs, cells were treated with 10 μM solasodine or dexamethasone (Dex), respectively, to analyze the possible mechanisms of action. A mouse model of bronchial asthma was constructed, and the mice were divided into control, OVA, OVA + Dex, OVA + solasodine (1 mg/kg) and OVA + solasodine (10 mg/kg) groups. The histopathological changes in the lungs of the mice were observed by staining with HE, Masson, and Tunel staining. ELISA assay was used to detect the differences between bronchoalveolar lavage uid (BALF) and serum. IL-4, IL-5, IL-1β, TNF-α and LTD-4 levels were detected by ELISA. BALF inammatory cells were detected by Wright staining and P-Fyn, P-Lyn and P-Syk protein expression in lung tissues were detected by Western blot.
Results: In TGF-β1-induced BMMCs, solasodine signicantly reduced the expression of P-Fyn, P-Lyn, and P-Syk, decreased the expression of cytokines IL-6, TNF-α, and LTC4 and calcium uptake, as well as inhibited mast cell degranulation. In ova mice, solasodine inhibited OVA-induced airway remodeling, production of IL-4, IL-5, IL-1β, TNF-α, and LTD-4, and degranulation of mast cells in asthmatic mice. Solasodine inhibited the activation of Fyn, Lyn, and Sky and reduced the number of inammatory cells such as eosinophils, lymphocytes, and neutrophils in lung tissues of asthmatic mice.
Conclusion: In this study, we found that solasodine could have a concentration-dependent therapeutic effect on OVA-induced allergic asthma, and solasodine could inhibit the release of mast cell degranulation signature mediator β-HEX and histamine, and the molecular mechanism of its ecacy might be related to its regulation of the intracellular calcium concentration and the IgE/FcεRI-mediated signaling pathways such as P-Fyn/Fyn, P-Lyn/Lyn, P-Syk/Syk, and etc.
Keywords: Solasodine, Mast cell, Airway inammation, Fyn-Lyn-Syk pathway
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