肠道IFNα4促进15-HETE饮食诱导的肺高血压
Grégoire Ruffenach1, Lejla Medzikovic2, Laila Aryan2
1Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, CHS BH-550 CHS, Los Angeles, CA, 90095-7115, USA. gr.ruffenach@laposte.net.
Respiratory research
|November 28, 2024
概括
饮食中的15-基酸 (15-HETE) 触发了肺动脉高血压 (PAH) 中的新型肠肺轴. 这一途径涉及增加IFN诱导蛋白44 (IFI44) 和 TRAIL表达,有助于PAH的发展.
科学领域:
- 肺血管重塑 肺血管重塑
- 肠肺轴在疾病发病过程中的作用
- 炎症信号通道的信号通道.
背景情况:
- 肺动脉高血压 (PAH) 涉及肺血管重塑和高压.
- 氧化脂肪酸,如15-基酸酸 (15-HETE),都涉及到PAH.
- 食15-HETE在小鼠中诱导肺高血压 (PH),这表明肠肺轴,但机制尚不清楚.
研究的目的:
- 为了阐明15-HETE诱导的肺动脉高血压中肠肺轴的机制.
- 确定参与该途径的关键分子参与者.
- 研究IFN诱导蛋白44 (IFI44) 和其调节者的作用.
主要方法:
- 对接受15-HETE饮食的小鼠的肺部和肠道RNA-seq数据和人类PAH患者的肺部数据进行比较的转录组分析.
- 对PAH患者的外周血液单核细胞 (PBMC) 的分析.
- 研究了IFI44和IFNα4在肠道和肺部的顺序表达.
- 在CD8细胞中检查了IFI44和瘤坏死因子相关的亡诱导联接体 (TRAIL) 之间的相关性.
- 使用IFN受体1-淘汰赛 (KO) 小鼠和IFI44基因沉默模型.
主要成果:
- 鉴定出IFI44是一种关键基因,在患有PAH的小鼠和人类中被调高.
- 15-HETE饮食增加了IFI44和IFNα4表达在肠道,然后是肺部.
- IFI44表达与小鼠和人类PH肺中的CD8细胞中TRAIL上调相关.
- 来自肠道细胞的IFNα4促进了CD8细胞中的IFI44表达.
- IFN受体1-KO小鼠在15-HETE饮食中没有发展PH.
- IFI44沉默阻止了PH的发展,并减少了肺 CD8 细胞中的 IFI44 和 TRAIL.
结论:
- 由15-HETE驱动的新型肠肺轴有助于肺动脉高血压.
- 该途径涉及在CD8细胞中IFI44的IFNα4介导诱导,导致TRAIL上调.
- 准这种肠肺轴可能为PAH提供新的治疗策略.
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