Human Cerebrospinal Fluid Macrophages and Outcome in Subarachnoid Hemorrhage

过去30年来，对动脉瘤性蛛网膜下腔出血的研究重点一直是 关于血管痉挛的病理生理学的认识和改善的尝试。 不幸的是，即使血管痉挛得到有效治疗，死亡率或 残疾。随后，出现了一个新的概念和更有效的临床试验终点 过去10年：迟发性脑缺血(DCI)，指新的脑梗塞导致 局灶性神经缺陷。研究表明，DCI的发生是独立的 至少与发病率有关。DCI的病因仍不确定，但我们认为 关注脑部炎症反应(CIR)对残留的持久血红素负荷的影响 可能是发起DCI的罪魁祸首。虽然存在许多独立的DCI关联， 没有以任何方式解释CIR。也许重点放在加快血肿解决上，因为 那么，寻找一些CIR的度量来提高DCI预测的精度是合乎情理的。 基于我们的SAH小鼠模型，我们发现大脑中的组织驻留巨噬细胞 负责CIR的大部分以及血肿的消退。在我们的提案中， 我们使用每个患者的脑脊液(CSF)组织中的巨噬细胞 研究DCI和血肿消退的居民来源。具体地说，我们把这些特殊的 巨噬细胞与人类神经细胞系的接触作为预测是否存在 病人可能患有DCI。我们使用流式细胞术来确定脑脊液中的巨噬细胞 吞噬大量红细胞以确定血肿是否会消失 更快，如果这会导致更少的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和 血肿解决基于个人的先天免疫配置文件。如果在 前瞻性试验，这些基于细胞的分析可以用于经验性地发现新的治疗方法 靶向可增强红细胞吞噬功能和减少神经元凋亡的药物 脑脊液巨噬细胞，在一个例子中“床边到工作台”的反向翻译。

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.