Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Duisburg, Germany.
Institute of Physiology, University Medicine Essen, University Duisburg-Essen, Duisburg, Germany.
Am J Physiol Endocrinol Metab. 2024 Oct 1;327(4):E422-E429. doi: 10.1152/ajpendo.00247.2024. Epub 2024 Aug 14.
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. 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.
组织在炎症部位经常会出现缺氧，这是由于灌注不良、大量免疫细胞募集和耗氧量增加所致。生物体通过各种基因的转录激活来适应这些低氧条件。事实上，低氧和炎症过程的转录反应之间存在显著的相互作用。这种相互作用，称为炎症性缺氧，在各种疾病中起着至关重要的作用，包括恶性肿瘤、慢性炎症性肺病和败血症。为了进一步阐明体内低氧和炎症之间的相互作用，并评估其在创新治疗中的潜力，我们的研究旨在研究急性低氧条件对炎症诱导的免疫反应的影响。为此，我们让健康的人类受试者在单次静脉（i.v.）注射 0.4ng/kg LPS 之前（低氧预处理）或之后暴露于低氧环境中。我们的数据表明，在 LPS 注射前暴露于低氧环境（低氧预处理）会放大促炎反应。这反映在体温升高、血浆去甲肾上腺素水平升高和促炎细胞因子（即 IL-6 和 TNF-α）的产生增加，与 LPS 对照条件相比。当参与者在 LPS 给药后暴露于低氧环境时，没有观察到这些影响，这表明低氧和炎症之间的相互作用高度依赖于两种刺激的时间。我们的研究结果表明，急性低氧（即低氧预处理）调节短暂性炎症，导致健康人类受试者的促炎反应增强。这凸显了进一步研究的必要性，以了解各种缺氧诱导因子（HIF）相关炎症性疾病的病理学，并开发合适的创新治疗方法。据我们所知，这是第一项研究低氧预处理或 LPS 给药后对健康人类受试者内毒素诱导的炎症反应的影响的体内研究。数据表明，低氧预处理放大了促炎反应，这反映在体温升高、血浆去甲肾上腺素水平升高和促炎细胞因子（即 IL-6 和 TNF-α）的产生增加，与 LPS 对照条件相比。
