Snyder Jessica M, Wood Thomas R, Corry Kylie, Moralejo Daniel H, Parikh Pratik, Juul Sandra E
Department of Comparative Medicine, University of Washington, Seattle, WA, United States.
Department of Pediatrics, University of Washington, Seattle, WA, United States.
Int J Dev Neurosci. 2018 Nov;70:25-33. doi: 10.1016/j.ijdevneu.2018.05.006. Epub 2018 May 20.
Inflammation caused by perinatal infection, superimposed with hypoxia and/or hyperoxia, appears to be important in the pathogenesis of preterm neonatal encephalopathy, with white matter particularly vulnerable during the third trimester. The associated inflammatory response is at least partly mediated through Toll-like receptor (TLR)-dependent mechanisms. Immunohistochemistry, gene expression, and behavioral studies were used to characterize white matter development and determine TLR3 and TLR4 expression and accumulation in the neonatal ferret brain. Expression of markers of white matter development increased significantly between postnatal day (P)1 and P10 (NG2, PDGFRα) or P15 (Olig2), and either remained elevated (NG2), or decreased again at P40 (PDGFRα, Olig2). Olig2 immunostaining within the internal capsule was also greatest at P15. Myelin basic protein (MBP) immunostaining and mRNA expression increased markedly from P15 to P40 and into adulthood, which correlated with increasing performance on behavioral tests (negative geotaxis, cliff aversion, righting reflex, and catwalk gait analysis). TLR4 and TLR3 positive staining was low at all ages, but TLR3 and TLR4 mRNA expression both increased significantly from P1 to P40. Following lipopolysaccharide (LPS) and hypoxia/hyperoxia exposure at P10, meningeal and parenchymal inflammation was seen, including an increase in TLR4 positive cells. These data suggest that the neuroinflammation associated with prematurity could be modeled in the newborn ferret.
围产期感染引起的炎症，叠加缺氧和/或高氧，在早产儿脑病的发病机制中似乎很重要，其中白质在妊娠晚期尤其脆弱。相关的炎症反应至少部分是通过Toll样受体（TLR）依赖性机制介导的。采用免疫组织化学、基因表达和行为学研究来表征白质发育，并确定新生雪貂脑内TLR3和TLR4的表达及积累情况。白质发育标志物的表达在出生后第（P）1天至P10天（NG2、血小板衍生生长因子受体α [PDGFRα]）或P15天（少突胶质细胞转录因子2 [Olig2]）之间显著增加，且要么保持升高（NG2），要么在P40天时再次下降（PDGFRα、Olig2）。内囊内的Olig2免疫染色在P15天时也最高。髓鞘碱性蛋白（MBP）免疫染色和mRNA表达从P15天到P40天及成年期均显著增加，这与行为测试（负趋地性、悬崖回避、翻正反射和猫步步态分析）表现的提高相关。TLR4和TLR3阳性染色在所有年龄段都很低，但TLR3和TLR4 mRNA表达从P1天到P40天都显著增加。在P10天时暴露于脂多糖（LPS）和缺氧/高氧后，可见脑膜和实质炎症，包括TLR4阳性细胞增加。这些数据表明，与早产相关的神经炎症可以在新生雪貂中建模。
