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首页> 外文期刊>Journal of neuroinflammation >Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep
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Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep

机译：局部缺氧缺血性早产绵羊的脑部炎症和周围免疫系统的动员

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Background Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of brain injury in preterm infants. Preterm HIE is predominantly caused by global hypoxia-ischemia (HI). In contrast, focal ischemia is most common in the adult brain and known to result in cerebral inflammation and activation of the peripheral immune system. These inflammatory responses are considered to play an important role in the adverse outcomes following brain ischemia. In this study, we hypothesize that cerebral and peripheral immune activation is also involved in preterm brain injury after global HI. Methods Preterm instrumented fetal sheep were exposed to 25 minutes of umbilical cord occlusion (UCO) (n = 8) at 0.7 gestation. Sham-treated animals (n = 8) were used as a control group. Brain sections were stained for ionized calcium binding adaptor molecule 1 (IBA-1) to investigate microglial proliferation and activation. The peripheral immune system was studied by assessment of circulating white blood cell counts, cellular changes of the spleen and influx of peripheral immune cells (MPO-positive neutrophils) into the brain. Pre-oligodendrocytes (preOLs) and myelin basic protein (MBP) were detected to determine white matter injury. Electro-encephalography (EEG) was recorded to assess functional impairment by interburst interval (IBI) length analysis. Results Global HI resulted in profound activation and proliferation of microglia in the hippocampus, periventricular and subcortical white matter. In addition, non-preferential mobilization of white blood cells into the circulation was observed within 1 day after global HI and a significant influx of neutrophils into the brain was detected 7 days after the global HI insult. Furthermore, global HI resulted in marked involution of the spleen, which could not be explained by increased splenic apoptosis. In concordance with cerebral inflammation, global HI induced severe brain atrophy, region-specific preOL vulnerability, hypomyelination and persistent suppressed brain function. Conclusions Our data provided evidence that global HI in preterm ovine fetuses resulted in profound cerebral inflammation and mobilization of the peripheral innate immune system. These inflammatory responses were paralleled by marked injury and functional loss of the preterm brain. Further understanding of the interplay between preterm brain inflammation and activation of the peripheral immune system following global HI will contribute to the development of future therapeutic interventions in preterm HIE.
机译：背景缺氧缺血性脑病（HIE）是早产儿脑损伤的最重要原因之一。早产HIE主要由整体缺氧缺血（HI）引起。相反，局灶性局部缺血在成年大脑中最常见，已知会导致脑部炎症和激活外周免疫系统。这些炎性反应被认为在脑缺血后的不良后果中起重要作用。在这项研究中，我们假设在整体HI后，大脑和外周免疫激活也参与了早发性脑损伤。方法早产器械胎儿绵羊在0.7孕时暴露于脐带闭塞（UCO）（n = 8）25分钟。假治疗的动物（n = 8）用作对照组。对脑切片进行电离钙结合衔接子分子1（IBA-1）染色，以研究小胶质细胞的增殖和活化。通过评估循环白细胞计数，脾脏细胞变化和外周免疫细胞（MPO阳性中性粒细胞）流入大脑，研究了外周免疫系统。检测前少突胶质细胞（preOLs）和髓鞘碱性蛋白（MBP）以确定白质损伤。记录脑电图（EEG）以通过间发间隔（IBI）长度分析评估功能障碍。结果整体HI导致海马，脑室周围和皮层下白质中小胶质细胞的深度活化和增殖。另外，在全身性HI后1天内观察到白细胞非优先动员进入循环，并且在全身性HI损伤后7天检测到大量嗜中性白细胞流入大脑。此外，整体性HI导致脾脏明显的内卷，这不能通过脾细胞凋亡的增加来解释。与脑部炎症相一致，整体性HI导致严重的脑萎缩，特定区域的preOL易损性，髓鞘过少和持续的脑功能受抑制。结论我们的数据提供了证据，即早产绵羊胎儿的整体HI导致严重的脑部炎症和周围先天免疫系统的动员。这些炎症反应与早产大脑的明显损伤和功能丧失并行。全面了解HI后，早产儿脑炎症与周围免疫系统激活之间的相互作用的进一步理解将有助于早产HIE的未来治疗干预的发展。

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