健康男性在服用内毒素之前的急性缺氧状态会导致促炎细胞因子反应的增加。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM American journal of physiology. Endocrinology and metabolism Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI:10.1152/ajpendo.00247.2024
Marie Jakobs, Bastian Tebbe, Anna Lena Friedel, Tina Schönberger, Harald Engler, Benjamin Wilde, Joachim Fandrey, Tina Hörbelt-Grünheidt, Manfred Schedlowski
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引用次数: 0

摘要

在炎症部位,由于灌注不良、免疫细胞大量招募和耗氧量增加,组织经常会出现缺氧。生物体通过各种基因的转录激活来适应这些缺氧条件。事实上,低氧和炎症过程的转录反应之间存在着明显的相互影响。这种相互作用被命名为炎症性缺氧,在恶性肿瘤、慢性炎症性肺病和败血症等多种疾病中起着至关重要的作用。为了进一步阐明体内缺氧与炎症之间的相互影响,并评估其对创新疗法的潜力,我们的研究旨在调查急性缺氧条件对炎症诱导的免疫反应的影响。为此,我们让健康人在静脉注射 0.4 纳克/千克 LPS 之前(缺氧启动)或之后暴露于缺氧环境中。我们的数据显示,在注射 LPS 之前暴露于低氧环境(低氧启动)会扩大促炎反应。与 LPS 控制条件相比,体温、血浆去甲肾上腺素水平和促炎细胞因子(即 IL-6 和 TNF-α)的产生均有所增加。当参与者在服用 LPS 后暴露于低氧环境时,并没有观察到这些影响,这表明低氧和炎症之间的相互作用在很大程度上取决于两种刺激的时间。我们的研究结果表明,急性缺氧(即缺氧引物)会调节瞬时炎症,导致健康人的促炎症反应增强。这凸显了进一步研究的必要性,以了解各种与 HIF 相关的炎症性疾病的病理,并开发合适的创新疗法。
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Acute hypoxic conditions preceding endotoxin administration result in an increased proinflammatory cytokine response in healthy men.

Tissues often experience hypoxia at sites of inflammation due to malperfusion, massive immune cell recruitment, and increased oxygen consumption. Organisms adapt to these hypoxic conditions through the transcriptional activation of various genes. In fact, there is significant crosstalk between the transcriptional responses to hypoxia and inflammatory processes. This interaction, named inflammatory hypoxia, plays a crucial role in various diseases including malignancies, chronic inflammatory lung diseases, and sepsis. To further elucidate the crosstalk between hypoxia and inflammation in vivo and assess its potential for innovative therapies, our study aimed at investigating the impact of acute hypoxic conditions on inflammation-induced immune responses. To this end, we exposed healthy human subjects to hypoxia either before (hypoxia priming) or after a single intravenous (i.v.) injection of 0.4 ng/kg LPS. Our data show that hypoxia exposure prior to LPS injection (hypoxia priming) amplified the proinflammatory response. This was reflected by an increase in body temperature, plasma noradrenaline levels, and the production of proinflammatory cytokines (i.e., IL-6 and TNF-α), compared with LPS control conditions. These effects were not observed when participants were exposed to hypoxia after LPS administration, demonstrating that the interaction between hypoxia and inflammation highly depends on the timing of both stimuli. Our findings suggest that acute hypoxia (i.e., hypoxia priming) modulates transient inflammation, leading to an enhanced proinflammatory response in healthy human subjects. This highlights the need for further investigations to understand the pathology of various hypoxia-inducible factor (HIF)-associated inflammatory diseases and to develop suitable, innovative therapies.NEW & NOTEWORTHY To our knowledge, this is the first in vivo study investigating the effects of hypoxia preceding (hypoxia priming) or following LPS administration on the endotoxin-induced inflammatory response in healthy human subjects. The data show that hypoxia priming amplified the proinflammatory response, reflected by an increased body temperature, increased plasma noradrenaline levels, and higher production of proinflammatory cytokines (i.e., IL-6 and TNF-α) compared with LPS control conditions.

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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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