Department of Pediatric Surgery, University of Texas Health Science Center at Houston, USA.
Department of Diagnostic and Interventional Imaging, McGovern Medical School at the University of Texas Health Science Center at Houston, USA.
Exp Neurol. 2023 Sep;367:114472. doi: 10.1016/j.expneurol.2023.114472. Epub 2023 Jun 17.
Inflammation and white matter injury are consequences of neonatal intraventricular hemorrhage (IVH). Both white matter and the neuroimmune system are developing during the time which IVH occurs and its consequences develop. IVH has been studied in many different animal models; however, the effects of IVH occurring at different developmental time points in the same model have not been examined. Understanding how the timing of IVH affects outcome may provide important insights into both IVH pathophysiology and innate immune development.
We used intraventricular injection of lysed whole blood to model neonatal IVH in postnatal day (P)2 and P5 rats. Flow cytometry was used to detect innate immune activation. MRI was used to screen animals for the development of increased ventricular size. Immunohistochemistry for myelin basic protein was used to quantify white matter and corpus callosum thickness.
P5 animals exhibited significant increases in several measures of classically pro-inflammatory innate immune activation that P2 animals did not. Animals with IVH induced at P5 also developed ventricular enlargement visible on MRI whereas animals with IVH induced at P2 did not. On histological analysis, there were no significant effects of IVH in P2 animals, but IVH in P5 animals reduced white matter labeling and corpus callosum thickness.
IVH induces a strong innate inflammatory response in P5 as well as changes in ventricular size and reduction of white matter. P2 animals do not exhibit significant changes in innate immune activation or white matter structure after IVH. This suggests that white matter pathology from IVH is due in part to innate immune activation; and that the developmental stage of the innate immune system is a key determinant of IVH pathology.
炎症和白质损伤是新生儿脑室出血（IVH）的后果。白质和神经免疫系统在发生 IVH 及其后果发展的时间内都在发育。IVH 已经在许多不同的动物模型中进行了研究；然而，同一模型中不同发育时间点发生的 IVH 的影响尚未被研究。了解 IVH 的发生时间如何影响结果，可能为 IVH 病理生理学和先天免疫发育提供重要的见解。
我们使用裂解全血脑室注射在出生后第 2 天（P2）和第 5 天（P5）的大鼠中建立新生儿 IVH 模型。使用流式细胞术检测先天免疫激活。使用 MRI 筛选动物以检测脑室大小增加。使用髓鞘碱性蛋白免疫组化定量白质和胼胝体厚度。
P5 动物表现出几种经典促炎先天免疫激活的显著增加，而 P2 动物则没有。在 P5 诱导 IVH 的动物中也可见到 MRI 上脑室扩大，而在 P2 诱导 IVH 的动物中则没有。组织学分析显示，P2 动物的 IVH 没有明显影响，但 P5 动物的 IVH 减少了白质标记和胼胝体厚度。
IVH 在 P5 诱导强烈的先天炎症反应，以及脑室大小变化和白质减少。P2 动物在 IVH 后没有表现出先天免疫激活或白质结构的显著变化。这表明 IVH 的白质病变部分归因于先天免疫激活；并且先天免疫系统的发育阶段是 IVH 病理的关键决定因素。
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