eNAMPT/TLR4信号驱动PAH细胞表型切换和肺血管重塑
Mohamed Ahmed1, Shaira L Kee2, Nahla Zaghloul1
1Department of Pediatrics, Division of Neonatology, University of Florida College of Medicine, Gainesville, FL, USA.
在临床前模型中准尼古丁胺胺酸转移酶 (eNAMPT) /TLR4信号与ALT-100 mAb逆转肺高血压 (PH) 和血管重塑. 这种方法改善了细胞表型切换,提供了潜在的治疗策略.
科学领域:
- 肺高血压研究 肺高血压研究
- 血管生物学 血管生物学
- 免疫学 免疫学 免疫学
背景情况:
- 由细胞表型切换驱动的肺动脉高血压 (PAH) 血管改造是一个治疗挑战.
- 尼古丁胺胺酸基转移酶 (eNAMPT) /托尔类受体4 (TLR4) 信号传递与肺高血压 (PH) 病理生物学有关.
- 使用ALT-100 mAb的eNAMPT中和在临床前PH模型中进行了探索.
研究的目的:
- 研究eNAMPT/TLR4信号在PH细胞表型切换中的作用.
- 在临床前PH模型中评估ENAMPT中和抗体 (ALT-100 mAb) 的治疗疗效.
- 评估ALT-100 mAb对内皮细胞,光滑肌细胞和单细胞/巨细胞的影响.
主要方法:
- 建立了由单色素 (MCT) 或缺氧/苏根 (Hy/Su) 诱导的PH的临床前小鼠模型.
- 从第4周开始,老鼠接受了IgG或ALT-100 mAb的皮下注射.
- 在血动力学和组织学上评估PH严重程度,在第42天通过单细胞RNA测序 (scRNAseq) 分析肺组织.
主要成果:
- 在MCT-PH和Hy/Su-PH大鼠中,ALT-100 mAb显著减轻了PH严重程度,包括血液动力学,组织学和血管重塑指数.
- scRNAseq显示,Hy/Su暴露促进了内皮细胞转移到介质酶细胞 (EndMT),光滑肌肉细胞增殖和单细胞分化为巨细胞.
- 用ALT-100 mAb治疗改善了Hy/Su-PH大鼠中的这些细胞表型切换事件.
结论:
- 自克林和对克林eNAMPT/TLR4信号驱动器加速了PH中的细胞表型切换.
- 这种信号通路代表了一种可用药物的标,用于逆转PH的血管重塑.
- ALT-100 mAb通过减轻PH和相关的细胞变化,证明了治疗潜力.
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