Department of Neonatology, Tübingen University Children's Hospital, Tübingen, Germany.
Department of Neonatology, Heidelberg University Children's Hospital, Heidelberg, Germany.
Pediatr Res. 2023 Mar;93(4):870-877. doi: 10.1038/s41390-022-02193-7. Epub 2022 Jul 29.
Infections are a major cause for morbidity and mortality in neonates; however, the underling mechanisms for increased infection susceptibility are incompletely understood. Hypoxia, which is present in inflamed tissues, has been identified as an important activation signal for innate immune cells in adults and is mainly mediated by hypoxia-inducible factor 1α (HIF-1α). Fetal tissue pO physiologically is low but rises immediately after birth.
In this study, the effect of low oxygen partial pressure (pO) on HIF-1α expression and its targets phagocytosis, reactive oxygen species (ROS) production and vascular endothelial growth factor (VEGF) secretion was compared in vitro between immune cells from adult peripheral blood and cord blood using anoxia, HIF-1α stabilizer desferroxamin (DFO) and E. coli as stimuli.
We show that anoxia-induced HIF-1α protein accumulation, phagocytosis, ROS-production and VEGF-expression were greatly diminished in cord blood compared to adult cells. E. coli led to HIF-1α gene expression in adult and cord blood immune cells; however, cord blood cells failed to accumulate HIF-1α protein and VEGF upon E. coli stimulation.
Taken together, our results show a diminished activation of cord blood immune cells by low pO, which might contribute to impaired reactivity in the context of infection.
Neonatal immune cells do not accumulate HIF-1α under low oxygen partial pressure leading to decreased phagocytosis and decreased ROS production. We demonstrate a previously unknown mechanism of reduced activation of neonatal immune cells in the context of an inflammatory response. This could contribute to the increased susceptibility of newborns and preterm infants to infection.
感染是新生儿发病率和死亡率的主要原因；然而，增加感染易感性的潜在机制尚未完全阐明。在炎症组织中存在的缺氧已被确定为成人固有免疫细胞的重要激活信号，主要由缺氧诱导因子 1α（HIF-1α）介导。胎儿组织的 pO 生理上较低，但出生后立即升高。
在这项研究中，使用缺氧、HIF-1α 稳定剂地拉罗司（DFO）和大肠杆菌作为刺激物，比较了成人外周血和脐血免疫细胞中低氧分压（pO）对 HIF-1α 表达及其靶标吞噬作用、活性氧（ROS）产生和血管内皮生长因子（VEGF）分泌的影响。
我们表明，与成人细胞相比，缺氧诱导的 HIF-1α 蛋白积累、吞噬作用、ROS 产生和 VEGF 表达在脐血中大大减少。大肠杆菌导致成人和脐血免疫细胞中 HIF-1α 基因表达；然而，大肠杆菌刺激后，脐血细胞未能积累 HIF-1α 蛋白和 VEGF。
总之，我们的结果表明，低 pO 对脐血免疫细胞的激活减弱，这可能导致感染时反应性受损。
新生儿免疫细胞在低氧分压下不会积累 HIF-1α，导致吞噬作用降低和 ROS 产生减少。我们证明了新生儿免疫细胞在炎症反应背景下激活减少的先前未知机制。这可能导致新生儿和早产儿对感染的易感性增加。
