Zamorano Miriam, Olson Scott D, Haase Candice, Cox Charles S, Miller Brandon A
University of Texas Health Science Center at Houston.
Res Sq. 2023 Jan 27:rs.3.rs-2512127. doi: 10.21203/rs.3.rs-2512127/v1.
Inflammation and white matter injury are consequences of neonatal intraventricular hemorrhage (IVH). Both white matter and the neuroimmune system are developing during which IVH and its consequences occur. IVH has been studied in many different animal models; however, the effects of IVH occurring at different developmental time points in the same model has not been examined. Examining how the timing of IVH affects the ultimate outcome of IVH may provide important insights into IVH pathophysiology. 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 assess white matter pathology. The acute response of the innate immune system at these time points differed, with P5 animals exhibiting 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 induced a reduction in several measures of white matter integrity. IVH induces a strong innate inflammatory response in P5 animals that correlates with changes in ventricular size and white matter. P2 animals did not exhibit any significant changes in innate immune activation or white matter structure after IVH. This suggests that the 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内出血（IVH）的后果。白质和神经免疫系统在IVH及其后果发生期间都在发育。IVH已在许多不同的动物模型中进行了研究；然而，在同一模型中不同发育时间点发生的IVH的影响尚未得到研究。研究IVH的发生时间如何影响IVH的最终结果可能为IVH的病理生理学提供重要见解。我们通过向出生后第2天（P2）和第5天（P5）的大鼠脑室内注射裂解的全血来模拟新生儿IVH。使用流式细胞术检测先天性免疫激活。使用MRI筛选动物以观察脑室大小增加的情况。使用髓鞘碱性蛋白免疫组织化学评估白质病理。这些时间点的先天性免疫系统的急性反应有所不同，P5动物在经典促炎先天性免疫激活的几个指标上表现出显著增加，而P2动物则没有。P5期诱导IVH的动物在MRI上也出现了脑室扩大，而P2期诱导IVH的动物则没有。在组织学分析中，IVH对P2动物没有显著影响，但P5动物的IVH导致白质完整性的几个指标降低。IVH在P5动物中诱导了强烈的先天性炎症反应，这与脑室大小和白质的变化相关。IVH后，P2动物在先天性免疫激活或白质结构方面没有表现出任何显著变化。这表明IVH引起的白质病理部分归因于先天性免疫激活；并且先天性免疫系统的发育阶段是IVH病理的关键决定因素。
