Human Cerebrospinal Fluid Macrophages and Outcome in Subarachnoid Hemorrhage

在过去的30年里，蛛网膜下腔出血的研究重点是 了解血管痉挛的病理生理学，并试图改善它。 不幸的是，即使血管痉挛得到有效治疗， 残疾。随后，一个新的概念和更有效的临床试验终点出现了 在过去的10年中：迟发性脑缺血（DCI），指的是新的梗死， 局灶性神经功能缺损研究表明，DCI的发生独立于 至少与发病率有关DCI的原因仍然不确定，但我们相信， 重点关注脑炎症反应（CIR）的持续血红素负担， 很可能是发起DCI的罪魁祸首虽然存在许多独立的DCI协会， 没有一个能解释CIR可能重点关注加速血肿消退， 以及找到CIR的某种度量以增加DCI预测的准确性是合适的。 基于我们的SAH小鼠模型，我们发现脑组织中的巨噬细胞 是大部分CIR和血肿消退的原因。在我们的提议中， 我们使用每个患者的脑脊液（CSF）巨噬细胞， 居民起源研究DCI和血肿解决方案。具体来说，我们把这些特殊的 巨噬细胞与人神经元细胞系接触，作为预测是否存在神经元细胞系的一种方法。 患者可能患有DCI。我们使用流式细胞术来确定CSF中的巨噬细胞是否 吞噬大量红细胞，以确定血肿是否会消退 更快，并且如果这导致更少的DCI。 我们相信这些研究可以提供一种个性化的方法来预测DCI， 血肿解决方案的基础上，一个人的先天免疫概况。如果在 前瞻性试验，这些基于细胞的测定可用于经验性地发现新的治疗方法， 靶点的药物可以增强红细胞吞噬作用和减少神经元凋亡， CSF巨噬细胞，在"床边到工作台"反向翻译的示例中。

The focus of research in aneurysmal subarachnoid hemorrhage for the last 30 years has been on understanding the pathophysiology of vasospasm and attempts to ameliorate it. Unfortunately, even when vasospasm is effectively treated, there is no improvement in death or disability. Subsequently, a novel concept and more effective endpoint for clinical trials emerged over the last 10 years: delayed cerebral ischemia (DCI), referring to new infarctions causing focal neurological deficits. Studies have shown that the occurrence of DCI is independently associated with morbidity, at least. The causes of DCI remains uncertain, but we believe that a focus on the cerebral inflammatory response (CIR) to the persistent heme burden that remains is a likely culprit for the initiation of DCI. While many independent associations for DCI exist, none account for the CIR in any way. Perhaps a focus on expedited hematoma resolution as well as finding some measure of the CIR to increase accuracy of DCI prediction is in order. Based on our mouse model of SAH, we found that the tissue resident macrophages of the brain are responsible for the majority of the CIR as well as for hematoma resolution. In our proposal, we use each individual patient’s cerebrospinal fluid (CSF) macrophages that are of tissue resident origin to study DCI and hematoma resolution. Specifically, we put these special macrophages in contact with a human neuronal cell line as a way to predict whether or not a patient might have DCI. We use flow cytometry to determine if the macrophages in the CSF are phagocytosing significant amounts of red blood cells to determine if the hematoma will resolve faster, and if this results in less DCI. We believe that these studies could provide a personalized approach to predicting DCI and hematoma resolution based on an individual’s innate immune profile. If validated in a prospective trial, these cell-based assays could be used to empirically discover new therapeutic targets for agents that could enhance RBC phagocytosis and reduce neuronal apoptosis by CSF macrophages, in an example of “bedside to bench” reverse translation.