Brunse Anders, Abbaspour Afrouz, Sangild Per Torp
Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
Dev Neurosci. 2018;40(3):198-208. doi: 10.1159/000488979. Epub 2018 Jun 6.
Necrotizing enterocolitis (NEC) increases the risk of brain injury and impaired neurodevelopment. Rapid brain maturation prior to birth may explain why preterm brains are particularly vulnerable to serious infections. Using pigs as models, we hypothesized that preterm birth was associated with altered blood-cerebrospinal fluid (CSF) barrier (BCSFB) function and cerebral structural deficits, and that NEC was associated with systemic inflammation, BCSFB disruption, and neuroinflammation. First, cesarean-delivered preterm and term pigs (n = 43-44) were euthanized at birth to investigate BCSFB function and markers of brain structural maturation, or on day 5 to measure markers of blood-brain barrier maturation in the hippocampus and striatum (experiment 1). Next, preterm pigs (n = 162) were fed increasing volumes of infant formula to assess NEC lesions, systemic inflammation, BCSFB permeability, cerebral histopathology, hippocampal micro-glial density, and cytokine levels on day 5 (experiments 2 and 3). In experiment 1, preterm newborns had increased CSF-plasma ratios of albumin and raffinose, reduced CSF glucose levels, as well as increased cerebral hydration and reduced white matter myelination compared with term animals. We observed lower hippocampal (but not striatal) perivascular astrocyte coverage for the first 5 days after preterm birth, accompanied by altered cell junction protein levels. In experiments 2 and- 3, piglets with severe NEC lesions showed reduced blood thrombocytes and increased plasma C-reactive protein and interleukin-6 levels. NEC was associated with increased CSF-plasma albumin and raffinose ratios, reduced CSF leukocyte numbers, and increased cerebral hydration. In the hippocampus, NEC was associated with pyramidal neuron loss and increased interleukin-6 levels. In the short term, NEC did not affect cerebral myelination or microglia density. In conclusion, altered BCSFB properties and brain structural deficits were observed in pigs after preterm birth. Acute gastrointestinal NEC lesions were associated with systemic inflammation, increased BCSFB permeability and region-specific neuronal damage. The results demonstrate the importance of early interventions against NEC to prevent brain injury in preterm infants.
坏死性小肠结肠炎（NEC）会增加脑损伤和神经发育受损的风险。出生前大脑的快速成熟可能解释了为什么早产的大脑特别容易受到严重感染的影响。以猪为模型，我们假设早产与血脑脊髓液（CSF）屏障（BCSFB）功能改变和脑结构缺陷有关，而NEC与全身炎症、BCSFB破坏和神经炎症有关。首先，剖宫产的早产和足月仔猪（n = 43 - 44）在出生时安乐死，以研究BCSFB功能和脑结构成熟的标志物，或在第5天测量海马体和纹状体中血脑屏障成熟的标志物（实验1）。接下来，给早产仔猪（n = 162）喂食逐渐增加量的婴儿配方奶粉，以评估第5天的NEC病变、全身炎症、BCSFB通透性、脑组织病理学、海马体小胶质细胞密度和细胞因子水平（实验2和3）。在实验1中，与足月动物相比，早产新生儿的脑脊液 - 血浆白蛋白和棉子糖比率增加，脑脊液葡萄糖水平降低，脑含水量增加，白质髓鞘形成减少。我们观察到早产出生后的前5天，海马体（而非纹状体）的血管周围星形胶质细胞覆盖率较低，同时细胞连接蛋白水平发生改变。在实验2和3中，患有严重NEC病变的仔猪血小板减少，血浆C反应蛋白和白细胞介素 - 6水平升高。NEC与脑脊液 - 血浆白蛋白和棉子糖比率增加、脑脊液白细胞数量减少以及脑含水量增加有关。在海马体中，NEC与锥体细胞丢失和白细胞介素 - 6水平升高有关。短期内，NEC不影响脑髓鞘形成或小胶质细胞密度。总之，早产仔猪出现了BCSFB特性改变和脑结构缺陷。急性胃肠道NEC病变与全身炎症、BCSFB通透性增加和区域特异性神经元损伤有关。结果表明早期干预NEC对预防早产儿脑损伤的重要性。
