PAR1通过通过RhoA/ROCK信号通路调解ERM酸化来调节败血症诱导的血管内皮屏障功能障碍
Linjun Zhao1, Jiahui Hu2, Pingping Zheng1
1Department of Emergency, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medical, 261 Huansha Rd, Hangzhou City 310006, China.
International immunopharmacology
|October 8, 2023
概括
蛋白酶激活受体1 (PAR1) 抑制通过稳定血管内皮屏障,防止败血症引起的器官衰竭. 这针对RhoA/ROCK通路,减少内皮膜的过性和多器官功能障碍综合征.
科学领域:
- 血管生物学 血管生物学
- 败血症病理生理学病理生理学
- 分子信号传输的方法
背景情况:
- 败血症通过血管内皮屏障的破坏导致器官衰竭.
- 蛋白酶激活受体1 (PAR1) 影响血管透性,但其在败血症中的作用尚未研究.
- 在败血症引起的内皮功能障碍中,PAR1的分子机制尚不清楚.
研究的目的:
- 研究PAR1在败血症引起的血管内皮屏障功能障碍中的作用.
- 为了阐明PAR1在败血症期间内皮膜超透性的分子机制.
- 在败血症模型中评估PAR1抑制的治疗潜力.
主要方法:
- 在体外研究中,使用脂聚糖 (LPS) 刺激的人类静脉内皮细胞 (HUVEC) 来评估PAR1,ERM酸化和RhoA/ROCK信号.
- 在小鼠体内使用结和穿孔 (CLP) 的体内败血症模型,通过SCH79797.7抑制PAR1.
- 血管透性的分析 (FITC-dextran,埃文斯蓝),F-actin重组 (免疫光),蛋白质表达 (西部斑,免疫组织化学) 和器官病理 (HE染色).
主要成果:
- 在体外,LPS诱导的HUVEC中的PAR1激活促进了ERM酸化,F-actin重组和内皮透气性,PAR1或RhoA抑制可以逆转这些效应.
- 抑制PAR1降低了RhoA和ROCK的表达.
- 在体内,在CLP诱导的败血症小鼠中,PAR1抑制降低了ERM酸化,改善了血管内皮屏障功能障碍,改善了多器官功能障碍综合征 (MODS).
结论:
- 通过ERM酸化,PAR1激活有助于通过ERM酸化导致败血症中的内皮屏障功能障碍.
- RhoA/ROCK 信号通路是 PAR1 诱导的肠内膜屏障缺陷在败血症中的关键媒介.
- 抑制PAR1提供了一种潜在的治疗策略,通过恢复血管完整性来缓解败血症引起的器官损伤.
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