伊萨里丁E通过抑制威尔布兰德因子诱导的内皮透气性和血小板-内皮相互作用来预防败血症
Yao-Sheng Liu1, Wen-Liang Chen2, Yu-Wei Zeng1
1Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Marine drugs
|June 26, 2024
概括
伊萨里丁E (ISE) 通过抑制血小板激活和防止·威莱布兰德因子 (vWF) 增加内皮透气性,减少败血症死亡率和肺损伤. 这种海洋化合物针对败血症引起的器官功能障碍中的关键相互作用.
科学领域:
- 海洋天然产品 海洋天然产品
- 免疫学 免疫学 免疫学
- 血管生物学 血管生物学
背景情况:
- 败血症引起的内皮膜过性驱动多器官功能障碍.
- 升高的·威勒布兰德因子 (vWF) 通过与整合素αvβ3.3结合而加剧内皮透性.
- 针对vWF-整合素αvβ3通路提供了败血症的治疗策略.
研究的目的:
- 为了研究以沙里丁E (ISE) 的疗效,一种海洋衍生的循环赫克萨德,在败血症的小鼠模型中.
- 评估ISE对败血病死亡率,肺损伤和内皮膜超透性的影响.
- 阐明ISE保护作用背后的分子机制.
主要方法:
- 在小鼠中,以诱导败血症的Cecal Ligation and Puncture (CLP) 模型.
- 评估生存率,肺损伤,血小板减少和血管炎症.
- 对vWF释放,血小板激活标志物 (VAMP8,SNAP23) 和血小板内皮细胞相互作用的分析.
- 在体外研究中,使用脂聚糖 (LPS) 刺激的人体静脉内皮细胞 (HUVEC) 和人体血小板.
- 使用西伦吉提德药理上抑制整合素αvβ3.
主要成果:
- 根据剂量,ISE改善了生存率,并减轻了败血症引起的肺损伤,血小板减少和炎症.
- 通过降低VAMP8和SNAP23.3的调节,ISE抑制了激活血小板中的vWF释放.
- ISE抑制了血小板对LPS刺激的HUVEC的粘附,减少了vWF分泌和内皮透性.
- 通过抑制vWF与整合素αvβ3的结合来介导ISE对内皮透气性的保护作用,这表明αvβ3-FAK/Src通路的参与.
结论:
- 伊萨里丁E显示出显著的保护作用,防止败血症引起的死亡率和器官损伤.
- 通过抑制血小板激活,减少vWF释放和防止vWF介导的内皮过性来发挥ISE的功能.
- 通过向血小板-内皮相互作用和vWF-整体素αvβ3轴,ISE代表了治疗败血症的一种有前途的治疗剂.
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