Increasing Oxygen Partial Pressures Induce a Distinct Transcriptional Response in Human PBMC: A Pilot Study on the "Normobaric Oxygen Paradox".
Increasing Oxygen Partial Pressures Induce a Distinct Transcriptional Response in Human PBMC: A Pilot Study on the "Normobaric Oxygen Paradox".
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DOI：
10.3390/ijms22010458
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发表时间：
2021-01-05
影响因子：
5.6
通讯作者：
Balestra C
中科院分区：
文献类型：
--
作者：
Fratantonio D;Virgili F;Zucchi A;Lambrechts K;Latronico T;Lafère P;Germonpré P;Balestra C
术语“常压氧悖论”(NOP) 描述了高氧事件后对恢复常氧的反应，组织将其感知为缺氧，并导致缺氧诱导因子 1α (HIF-1α) 转录因子活性上调。这种反应的分子特征尚未完全表征。在此，我们报告了健康受试者暴露于轻度（MH）、高（HH）和极高（VHH）高氧（分别对应于30％、100％、140％O2）一小时后，人外周血单核细胞（PBMC）中氧敏感转录因子的激活时间趋势。我们的观察证实，MH 被认为是一种缺氧应激，其特征是 HIF-1α 和核因子（红细胞衍生 2）样 2 (NRF2) 的激活，但不是激活 B 细胞的核因子 kappa 轻链增强子 (NF-κB)。相反，HH 与 NOP 反应的逐渐丧失和氧化应激的增加相关，导致 NRF2 和 NF-kB 激活，并伴有谷胱甘肽 (GSH) 的合成。 VHH 后，HIF-1α 激活完全消失，氧化应激反应普遍存在，并伴有 NF-κB 激活。细胞内 GSH 和基质金属肽酶 9 (MMP-9) 血浆水平与转录因子激活模式平行，并在整个观察时间内保持升高状态。总之，我们的研究证实，在体内，MH 后恢复正常氧浓度被感知为以 HIF-1α 激活为特征的缺氧触发因素。相反，HH 和 VHH 会诱导氧化应激反应的转变，其特征是暴露后 24 小时内 NRF2 和 NF-κB 激活。
The term “normobaric oxygen paradox” (NOP), describes the response to the return to normoxia after a hyperoxic event, sensed by tissues as oxygen shortage, and resulting in up-regulation of the Hypoxia-inducible factor 1α (HIF-1α) transcription factor activity. The molecular characteristics of this response have not been yet fully characterized. Herein, we report the activation time trend of oxygen-sensitive transcription factors in human peripheral blood mononuclear cells (PBMCs) obtained from healthy subjects after one hour of exposure to mild (MH), high (HH) and very high (VHH) hyperoxia, corresponding to 30%, 100%, 140% O2, respectively. Our observations confirm that MH is perceived as a hypoxic stress, characterized by the activation of HIF-1α and Nuclear factor (erythroid-derived 2)-like 2 (NRF2), but not Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). Conversely, HH is associated to a progressive loss of NOP response and to an increase in oxidative stress leading to NRF2 and NF-kB activation, accompanied by the synthesis of glutathione (GSH). After VHH, HIF-1α activation is totally absent and oxidative stress response, accompanied by NF-κB activation, is prevalent. Intracellular GSH and Matrix metallopeptidase 9 (MMP-9) plasma levels parallel the transcription factors activation pattern and remain elevated throughout the observation time. In conclusion, our study confirms that, in vivo, the return to normoxia after MH is sensed as a hypoxic trigger characterized by HIF-1α activation. On the contrary, HH and VHH induce a shift toward an oxidative stress response, characterized by NRF2 and NF-κB activation in the first 24 h post exposure.
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影响因子：
5.5
作者：
De Bels, David;Tillmans, Frauke;Balestra, Costantino
通讯作者：
Balestra, Costantino
影响因子：
3.3
作者：
Cimino, F.;Balestra, C.;Virgili, F.
通讯作者：
Virgili, F.
影响因子：
11.4
作者：
Done AJ;Traustadóttir T
通讯作者：
Traustadóttir T
影响因子：
3.5
作者：
Cimino, Francesco;Speciale, Antonio;Saija, Antonina
通讯作者：
Saija, Antonina
影响因子：
4.6
作者：
Iannetta, Marco;Zingaropoli, Maria Antonella;Ciardi, Maria Rosa
通讯作者：
Ciardi, Maria Rosa