Cerebrospinal Fluid Dynamics in Posthemorrhagic Hydrocephalus in Neonates

摘要 生发基质出血(GMH)是指血管内未成熟的薄壁血管的出血。 早产儿的生发基质。出血性脑积水是一种常见但严重的后果。 来自葛兰素史克医院。然而，目前还没有有效的治疗方法，只有手术分流，这会造成巨大的 社会经济负担。因此，为了表征潜在的机制并确定潜在的治疗方法 目标是最重要的。脑脊液主要由脉络丛产生 并被蛛网下绒毛重新吸收，新生儿更多地通过淋巴系统重新吸收。GMH 结果导致血液产物分解、炎症和星形胶质细胞增生症，这可能损害脑室周围 纸巾。GMH后，负责维持正常脑脊液血流动力学的组织可能会受到损伤， 导致出血性脑积水。脉络丛专门用于脑脊液的产生和 调节血-脑脊液屏障。GMH后溶解红细胞的铁毒性可能导致增加 与脑脊液分泌有关的碳酸氢钠共转运体slc4a10的表达 脉络丛处脑脊液过度分泌。此外，淋巴脑脊液引流被认为起到了很大的作用。 在新生儿中的作用，因为蛛网膜下腔绒毛分布稀疏，其功能也可能受到影响 跟随GMH。淋巴系统涉及星形胶质细胞介导的脑脊液-间质液体(ISF)交换 Virchow-Robin空间，由星形细胞水通道蛋白-4驱动。此外，向内整流钾 通道4.1(Kir4.1)与星形胶质细胞中的水通道蛋白-4共同作用，调节渗透压梯度和 随后的水流动，但它在淋巴CSF-ISF交换中的作用尚未确定。星形胶质细胞增多症 GMH可能改变水通道蛋白-4和Kir4.1的表达或功能，扰乱淋巴CSF-ISF交换 从而减少脑脊液的重吸收。我们的总体假设是，在GMH之后，急性铁 超负荷通过诱导slc4a10和长期的 星形胶质细胞增生症损害了正常脑脊液通过淋巴系统的重吸收，导致后遗症 新生儿出血性脑积水。为了验证这一假设，我们将从两个具体的方面进行研究 目标。特异目的1：确定铁诱导脉络丛中slc4a10表达的作用 GMH后，导致脑脊液分泌增加。具体目标2：确定GMH诱导的作用 星形胶质细胞增生症和随之而来的Kir4.1和Aquaporin-4在扰乱脑脊液-ISF交换和 通过淋巴系统清除脑脊液。

Abstract Germinal matrix hemorrhage (GMH) is the bleeding from the thin-walled immature blood vessels in the germinal matrix of pre‑term infants. Post‑hemorrhagic hydrocephalus is a common but severe consequence from GMH. However, there is no effective treatment for this so far but surgical shunting, which causes a huge socioeconomic burden. Thus, to characterize the underlying mechanisms and identify the potential therapeutic targets are of the utmost importance. Cerebrospinal fluid (CSF) is mainly produced from the choroid plexus and reabsorbed by subarachnoid villi and to a greater extent in neonates, through the glymphatic system. GMH results in breakdown of blood products, inflammation and astrogliosis, which can damage periventricular tissues. Tissues responsible for maintaining normal CSF flow dynamics may be injured following GMH, contributing to post-hemorrhagic hydrocephalus. The choroid plexus is specialized for CSF production and regulating the blood-CSF barrier. Iron toxicity from lysed red blood cells after GMH may lead to increased expression of slc4a10, a sodium bicarbonate co-transporter responsible for CSF secretion, and consequent CSF over-secretion at the choroid plexus. Furthermore, glymphatic CSF drainage is postulated to play a great role in neonates, since subarachnoid villi are sparsely distributed, and its function may also be compromised following GMH. The glymphatic system involves astrocyte-mediated CSF-interstitial fluid (ISF) exchange in Virchow-Robin space, which is driven by astrocytic aquaporin-4. In addition, inwardly rectifying potassium channel 4.1 (Kir4.1) works in conjunction with aquaporin-4 in astrocytes for regulating osmotic gradients and consequent water flow, yet its role in glymphatic CSF-ISF exchange has not been established. Astrogliosis from GMH may alter aquaporin-4 and Kir4.1 expression or function, disrupting glymphatic CSF-ISF exchange and consequently reducing CSF reabsorption. Our overall hypothesis is that, following GMH, acute iron overload contributes to CSF overproduction at the choroid plexus by inducing slc4a10 and long-term astrogliosis impairs normal CSF reabsorption through the glymphatic system, leading to post- hemorrhagic hydrocephalus in neonates. To test this hypothesis, we will conduct our study in two specific aims. Specific Aim 1: Determine the role of iron-induced expression of slc4a10 at the choroid plexus after GMH, leading to increased CSF secretion. Specific Aim 2: Determine the role of GMH-induced astrogliosis and consequent Kir4.1 and aquaporin-4 expression in disrupting CSF-ISF exchange and CSF clearance through the glymphatic system.