Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
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DOI：
10.3791/53196
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发表时间：
2015-11-01
影响因子：
1.2
通讯作者：
Robinson, Shenandoah
中科院分区：
文献类型：
--
作者：
Jantzie, Lauren L.;Winer, Jesse L.;Robinson, Shenandoah
早产儿脑病（EoP）是一个涵盖与早产相关的中枢神经系统（CNS）异常的术语。为了最好地推进翻译目标，并发现新的治疗策略与早产相关的脑损伤，EoP的临床前模型必须包括在人类中观察到的产前整体损伤的类似机制，并涉及母-胎盘-胎儿系统的多个组成部分。理想情况下，模型应该在成熟动物中产生类似的功能缺陷谱，并概括病理生理学的多个方面。为了模拟人类全身性胎盘灌注缺陷，胎盘灌注不足和/或绒毛膜炎与病原体诱导的炎症在早期早产，我们开发了产前短暂全身缺氧缺血（TSHI）结合羊膜内脂多糖（LPS）的模型。在妊娠的Sprague道利大鼠中，在胚胎第18天（E18）通过子宫动脉闭塞的TSHI诱导与胎儿中增加的CNS损伤相关的分级胎盘灌注不足缺陷。当与羊膜内LPS注射结合时，胎盘炎症增加，CNS损伤与相关的白色物质、步态和成像异常复合。产前TSHI和TSHI+LPS产前损伤满足EoP模型的几个标准，包括重现子宫内损伤，引起神经元、少突胶质细胞和轴突的损失，亚板的损失，以及成年动物中的功能缺陷，其模拟在极早产儿中观察到的那些。此外，该模型允许解剖由不同损伤类型诱导的炎症。
Encephalopathy of prematurity (EoP) is a term that encompasses the central nervous system (CNS) abnormalities associated with preterm birth. To best advance translational objectives and uncover new therapeutic strategies for brain injury associated with preterm birth, preclinical models of EoP must include similar mechanisms of prenatal global injury observed in humans and involve multiple components of the maternal-placental-fetal system. Ideally, models should produce a similar spectrum of functional deficits in the mature animal and recapitulate multiple aspects of the pathophysiology. To mimic human systemic placental perfusion defects, placental underperfusion and/or chorioamnionitis associated with pathogen-induced inflammation in early preterm birth, we developed a model of prenatal transient systemic hypoxia-ischemia (TSHI) combined with intra-amniotic lipopolysaccharide (LPS). In pregnant Sprague Dawley rats, TSHI via uterine artery occlusion on embryonic day 18 (E18) induces a graded placental underperfusion defect associated with increasing CNS damage in the fetus. When combined with intra-amniotic LPS injections, placental inflammation is increased and CNS damage is compounded with associated white matter, gait and imaging abnormalities. Prenatal TSHI and TSHI+LPS prenatal insults meet several of the criteria of an EoP model including recapitulating the intrauterine insult, causing loss of neurons, oligodendrocytes and axons, loss of subplate, and functional deficits in adult animals that mimic those observed in children born extremely preterm. Moreover, this model allows for the dissection of inflammation induced by divergent injury types.