Liu Qian, Hua Lijuan, Bao Chen, Kong Luxia, Hu Jiannan, Liu Chao, Li Ziling, Xu Shuyun, Liu Xiansheng
Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Key Site of National Clinical Research Center for Respiratory Disease, Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Respiratory and Critical Care Medicine, Taikang Tongji (Wuhan) Hospital, Wuhan, China.
Front Pharmacol. 2022 May 5;13:885053. doi: 10.3389/fphar.2022.885053. eCollection 2022.
Regulation or restoration of therapeutic sensitivity to glucocorticoids is important in patients with steroid-resistant asthma. Spleen tyrosine kinase (Syk) is activated at high levels in asthma patients and mouse models, and small-molecule Syk inhibitors such as R406 show potent anti-inflammatory effects in the treatment of immune inflammatory diseases. Several downstream signaling molecules of Syk are involved in the glucocorticoid response, so we hypothesized that R406 could restore sensitivity to dexamethasone in severe steroid-resistant asthma. To discover the role of the Syk inhibitor R406 in glucocorticoid resistance in severe asthma. Steroid-resistant asthma models were induced by exposure of C57BL/6 mice to house dust mite (HDM) and β-glucan and by TNF-α administration to the bronchial epithelial cell line BEAS-2B. We evaluated the role of the Syk inhibitor R406 in dexamethasone (Dex)-insensitive airway inflammation. Pathological alterations and cytokines in the lung tissues and inflammatory cells in BALF were assessed. We examined the effects of Dex or R406 alone and in combination on the phosphorylation of MAPKs, glucocorticoid receptor (GR) and Syk, as well as the transactivation and transrepression induced by Dex in mouse lung tissues and BEAS-2B cells. Exposure to HDM and β-glucan induced steroid-resistant airway inflammation. The Syk inhibitor R406 plus Dex significantly reduced airway inflammation compared with Dex alone. Additionally, TNF-α-induced IL-8 production in BEAS-2B cells was not completely inhibited by Dex, while R406 markedly promoted the anti-inflammatory effect of Dex. Compared with Dex alone, R406 enhanced Dex-mediated inhibition of the phosphorylation of MAPKs and GR-Ser226 induced by allergens or TNF-α and . Moreover, R406 also restored the impaired expression and nuclear translocation of GRα induced by TNF-α. Then, the activation of NF-κB and decreased HDAC2 activity in the asthmatic model were further regulated by R406, as well as the expression of GILZ. The Syk inhibitor R406 improves sensitivity to dexamethasone by modulating GR. This study provides a reference for the development of drugs to treat severe steroid-resistant asthma.
调节或恢复对糖皮质激素的治疗敏感性在激素抵抗性哮喘患者中很重要。脾酪氨酸激酶（Syk）在哮喘患者和小鼠模型中高水平激活，小分子Syk抑制剂如R406在免疫炎症性疾病治疗中显示出强大的抗炎作用。Syk的几个下游信号分子参与糖皮质激素反应，因此我们假设R406可以恢复重度激素抵抗性哮喘对地塞米松的敏感性。为了发现Syk抑制剂R406在重度哮喘糖皮质激素抵抗中的作用。通过将C57BL/6小鼠暴露于屋尘螨（HDM）和β-葡聚糖以及向支气管上皮细胞系BEAS-2B给予TNF-α诱导激素抵抗性哮喘模型。我们评估了Syk抑制剂R406在对地塞米松（Dex）不敏感的气道炎症中的作用。评估了肺组织中的病理改变和细胞因子以及BALF中的炎症细胞。我们研究了单独或联合使用Dex或R406对MAPKs、糖皮质激素受体（GR）和Syk磷酸化的影响，以及Dex在小鼠肺组织和BEAS-2B细胞中诱导的反式激活和反式抑制。暴露于HDM和β-葡聚糖诱导了激素抵抗性气道炎症。与单独使用Dex相比，Syk抑制剂R406加Dex显著减轻了气道炎症。此外，TNF-α诱导的BEAS-2B细胞中IL-8的产生未被Dex完全抑制，而R406显著增强了Dex的抗炎作用。与单独使用Dex相比，R406增强了Dex介导的对由过敏原或TNF-α诱导的MAPKs磷酸化和GR-Ser226的抑制作用。此外，R406还恢复了由TNF-α诱导的GRα表达受损和核转位。然后，R406进一步调节了哮喘模型中NF-κB的激活和HDAC2活性的降低，以及GILZ的表达。Syk抑制剂R406通过调节GR提高对地塞米松的敏感性。本研究为治疗重度激素抵抗性哮喘的药物开发提供了参考。
