布雷波西提尼布是一种选择性TYK2/JAK1抑制剂,可减轻COPD中中性恋炎症和葡萄糖皮质体受体β表达
Barsha Baisakhi Nayak1, Thomas Bärnthaler1,2, Rishi Rajesh1
1Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria.
概括
这项研究表明,用布雷波西提尼布抑制Janus激酶/信号转换器和转录激活器 (JAK-STAT) 途径可以减少慢性阻塞性肺病 (COPD) 中的中性粒细胞炎症. 这种方法可以在严重的呼吸道炎症中克服皮质类固醇抵抗.
科学领域:
- 免疫学 免疫学 免疫学
- 呼吸系统医学 呼吸系统医学
- 药理学 药理学是指药理学的学科.
背景情况:
- 慢性阻塞性肺病 (COPD) 具有持续的气道炎症特征,由中性粒细胞驱动,通常对皮质类固醇有抗性.
- 介素-23 (IL-23) /介素-17A (IL-17A) 轴和Janus激酶/信号转换器和转录激活器 (JAK-STAT) 途径都与COPD的发病有关.
- TYK2和JAK1在中性粒细胞驱动的炎症和COPD中皮质类固醇耐药性的特定作用需要进一步阐明.
研究的目的:
- 研究IL-23/IL-17A轴在COPD中调节中性粒细胞功能的作用.
- 在COPD模型中评估双TYK2/JAK1抑制剂布雷波丁的治疗潜力.
- 检查布雷波西提尼布对中性粒细胞激活,IL-8释放和葡萄糖皮质体受体β (GRβ) 表达的影响.
主要方法:
- 用基因表达和流细胞测量来分析来自COPD患者和吸烟者的唾液细胞和中性粒细胞.
- 在体外实验中评估了IL-23和IL-17A对中性粒细胞激活和IL-8释放的影响,以及布雷波西提尼布的影响.
- 在体内研究评估了布雷波西提尼布在急性炎症模型中抑制中性粒细胞招募的疗效.
主要成果:
- 慢性肺炎患者和吸烟者在中性粒细胞中增加了TYK2和JAK1的表达和酸化.
- IL-23和IL-17A促进了中性粒细胞的激活和IL-8的释放,而布雷波西替尼则抑制了这一作用.
- 布雷波西替尼 (brepocitinib) 逆转了COPD患者和吸烟者的中性粒细胞中升高的GRβ表达,这是皮质类固醇耐药性的标志.
结论:
- JAK-STAT通路,特别是TYK2和JAK1,是COPD中中性粒细胞驱动的炎症和皮质类固醇耐药性的关键调解者.
- 布雷波西提尼布的双TYK2/JAK1抑制有效地减轻了IL-23/IL-17A诱导的炎症和COPD中的GRβ上调.
- 针对JAK-STAT通路提供了一个有希望的治疗策略,用于控制COPD中严重的呼吸道炎症.
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