Dell'Ovo Valeria, Rosenzweig Jason, Burd Irina, Merabova Nana, Darbinian Nune, Goetzl Laura
Department of Obstetrics and Gynecology, Center for Neural Repair and Rehabilitation, Shriners Hospitals Pediatric Research Center and Department of Obstetrics & Gynecology, Temple University School of Medicine, Philadelphia, PA.
Department of Obstetrics and Gynecology, Integrated Research Center for Fetal Medicine, Johns Hopkins University, Baltimore, MD.
Am J Obstet Gynecol. 2015 Sep;213(3):387.e1-10. doi: 10.1016/j.ajog.2015.05.007. Epub 2015 May 12.
The purpose of this study was to develop an animal model for intrapartum inflammation at term to investigate the interactions between maternal and fetal inflammatory responses and adverse neurologic outcome.
Lipopolysaccharide (160, 320, or 640 μg/kg) was administered intraperitoneally to day 20 term-pregnant Sprague Dawley rat dams 2, 4, and 6 hours before sample collection. Maternal outcomes included dam core temperature and plasma interleukin 6 (IL-6). Fetal outcomes included plasma IL-6, brain IL-6 messenger RNA expression, and brain IL-6 protein expression. Primary cortical cell cultures were prepared to examine neuronal morphologic condition. Neurite counts were obtained with the use of automated Sholl analysis.
Maternal plasma IL-6 levels peaked 2 hours after lipopolysaccharide stimulus and rapidly resolved, except for an observed low level persistence at 6 hours with 640 μg/kg. Fetal plasma and placental IL-6 expression also peaked rapidly but only persisted in placental samples. Fetal brain IL-6 RNA and protein expression was significantly higher than control litters at 6 hours after the exposure to both 320 μg/kg (P ≤ .05) and 640 μg/kg (P ≤ .01). Cortical cells from fetuses that were exposed for 6 hours to maternal systemic inflammation showed reduced neurite number and neurite length (P < .001) with increasing lipopolysaccharide dose.
Our results demonstrate that fetal brain injury follows isolated systemic maternal inflammation and that fetal brain inflammation lags after maternal stimulus, which creates a potential 4-hour clinical window for therapeutic intervention.
本研究旨在建立一种足月产时炎症的动物模型，以研究母体和胎儿炎症反应之间的相互作用以及不良神经学结局。
在样本采集前2、4和6小时，向孕20天的足月妊娠斯普拉格-道利大鼠母鼠腹腔内注射脂多糖（160、320或640μg/kg）。母体结局包括母鼠核心体温和血浆白细胞介素6（IL-6）。胎儿结局包括血浆IL-6、脑IL-6信使核糖核酸表达和脑IL-6蛋白表达。制备原代皮质细胞培养物以检查神经元形态状况。使用自动肖尔分析获得神经突计数。
脂多糖刺激后2小时，母体血浆IL-6水平达到峰值并迅速消退，但640μg/kg剂量组在6小时时观察到低水平持续存在。胎儿血浆和胎盘IL-6表达也迅速达到峰值，但仅在胎盘样本中持续存在。在暴露于320μg/kg（P≤0.05）和640μg/kg（P≤0.01）后6小时，胎儿脑IL-6核糖核酸和蛋白表达均显著高于对照组同窝幼崽。暴露于母体全身炎症6小时的胎儿的皮质细胞显示，随着脂多糖剂量增加，神经突数量和神经突长度减少（P<0.001）。
我们的结果表明，孤立的母体全身炎症会导致胎儿脑损伤，且胎儿脑炎症在母体刺激后出现延迟，这为治疗干预创造了一个潜在的4小时临床窗口期。
