肺内皮信号的循环控制通过NADPH氧化酶2-NLRP3路径发生
Shaon Sengupta1,2,3,4, Yool Lee4,5, Jian Qin Tao6
1Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Journal of biological rhythms
|September 15, 2025
概括
生物钟通过控制肺内皮细胞来调节肺炎. 通过活性氧物种 (ROS) 破坏这种时钟会加剧炎症,但抑制NADPH氧化酶2 (NOX2) 会恢复节律性.
科学领域:
- 肺部医学 肺部医学
- 时间生物学 时间生物学
- 免疫学 免疫学 免疫学
背景情况:
- 昼夜节律控制着24小时的生理周期,对恒温至关重要.
- 生物钟在肺内皮和肺炎中的作用在很大程度上是未知的.
- 肺内皮细胞是肺炎的关键调节者.
研究的目的:
- 为了研究生物钟对肺内皮的直接调节.
- 为了确定时钟在控制肺炎中的作用.
- 阐明连接昼夜节律,炎症和肺内皮的机制.
主要方法:
- 利用mPer2luciferase转基因小鼠监测肺动脉段和内皮细胞中的昼夜节律.
- 服用脂聚糖 (LPS) 诱导炎症,并观察其对昼夜节律的影响.
- 采用NADPH氧化酶2 (NOX2) 抑制和时钟突变模型 (Bmal1-/-,Cry1/2-/-) 来研究炎症途径.
- 分析了多态核核中性粒细胞 (PMN) 积累,ICAM-1表达和NLRP3炎症酶激活.
主要成果:
- 肺内皮细胞治疗破坏了肺内皮细胞的昼夜节律,通过NOX2.2通过ROS介导.
- 在LPS暴露后的肺内皮质中,NOX2抑制恢复了昼夜节律.
- LPS激活了NOX2-NLRP3信号轴,在野生类型小鼠中增加了PMN和ICAM-1.
- 由于NLRP3炎症酶激活,时钟突变体表现出基线PMN和ICAM-1的升高,LPS反应最小.
- 观察到一种双向关系:昼夜时钟调节炎症,而炎症通过NOX2改变昼夜节律.
结论:
- 生物钟直接调节肺内皮细胞的炎症反应.
- NOX2-NLRP3通路是关键的调解者,将昼夜干扰与肺炎联系起来.
- 针对肺内皮中的昼夜时钟机制,为与时钟中断相关的肺部疾病提供了潜在的治疗策略.
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