Inflammatory gene expression during acute high-altitude exposure.

The Journal of Physiology Pub Date : 2022-09-01 Epub Date: 2022-08-17 DOI:10.1113/JP282772
Kathy Pham, Shyleen Frost, Keval Parikh, Nikhil Puvvula, Britney Oeung, Erica C Heinrich
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引用次数: 9

Abstract

The molecular signalling pathways that regulate inflammation and the response to hypoxia share significant crosstalk and appear to play major roles in high-altitude acclimatization and adaptation. Several studies demonstrate increases in circulating candidate inflammatory markers during acute high-altitude exposure, but significant gaps remain in our understanding of how inflammation and immune function change at high altitude and whether these responses contribute to high-altitude pathologies, such as acute mountain sickness. To address this, we took an unbiased transcriptomic approach, including RNA sequencing and direct digital mRNA detection with NanoString, to identify changes in the inflammatory profile of peripheral blood throughout 3 days of high-altitude acclimatization in healthy sea-level residents (n = 15; five women). Several inflammation-related genes were upregulated on the first day of high-altitude exposure, including a large increase in HMGB1 (high mobility group box 1), a damage-associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury. Differentially expressed genes on the first and third days of acclimatization were enriched for several inflammatory pathways, including nuclear factor-κB and Toll-like receptor (TLR) signalling. Indeed, both TLR4 and LY96, which encodes the lipopolysaccharide binding protein (MD-2), were upregulated at high altitude. Finally, FASLG and SMAD7 were associated with acute mountain sickness scores and peripheral oxygen saturation levels on the first day at high altitude, suggesting a potential role of immune regulation in response to high-altitude hypoxia. These results indicate that acute high-altitude exposure upregulates inflammatory signalling pathways and might sensitize the TLR4 signalling pathway to subsequent inflammatory stimuli. KEY POINTS: Inflammation plays a crucial role in the physiological response to hypoxia. High-altitude hypoxia exposure causes alterations in the inflammatory profile that might play an adaptive or maladaptive role in acclimatization. In this study, we characterized changes in the inflammatory profile following acute high-altitude exposure. We report upregulation of novel inflammation-related genes in the first 3 days of high-altitude exposure, which might play a role in immune system sensitization. These results provide insight into how hypoxia-induced inflammation might contribute to high-altitude pathologies and exacerbate inflammatory responses in critical illnesses associated with hypoxaemia.

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急性高海拔暴露中的炎症基因表达。
调节炎症和缺氧反应的分子信号通路具有显著的串扰,似乎在高原适应和适应中发挥重要作用。一些研究表明急性高海拔暴露期间循环候选炎症标志物增加,但我们对炎症和免疫功能如何在高海拔变化以及这些反应是否导致急性高原病等高原病理的理解仍然存在重大差距。为了解决这个问题,我们采用了一种无偏的转录组学方法,包括RNA测序和NanoString直接数字mRNA检测,以确定健康海平面居民在3天的高海拔适应过程中外周血炎症谱的变化(n = 15;五位女性)。在高海拔暴露的第一天,几种炎症相关基因上调,包括HMGB1(高迁移率组框1)的大量增加,HMGB1是一种损伤相关分子模式(DAMP)分子,在组织损伤期间放大免疫反应。在驯化的第1天和第3天,几种炎症通路的差异表达基因富集,包括核因子-κB和toll样受体(TLR)信号传导。事实上,编码脂多糖结合蛋白(MD-2)的TLR4和LY96在高海拔地区都出现了上调。最后,FASLG和SMAD7与急性高山病评分和高海拔第一天的外周氧饱和度水平相关,提示免疫调节可能在高原缺氧反应中发挥作用。这些结果表明急性高海拔暴露上调炎症信号通路,并可能使TLR4信号通路对随后的炎症刺激敏感。重点:炎症在缺氧的生理反应中起着至关重要的作用。高海拔缺氧暴露导致炎症谱的改变,这可能在适应环境中起适应或不适应作用。在这项研究中,我们描述了急性高海拔暴露后炎症谱的变化。我们报告了在高海拔暴露的前3天,新的炎症相关基因的上调,这可能在免疫系统致敏中发挥作用。这些结果为低氧诱导的炎症如何促进高原病理和加剧与低氧血症相关的危重疾病的炎症反应提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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