Cellular Neuroinflammation in Acute Brain Injury

导致急性脑损伤的情况，如创伤和脑出血，是导致死亡和残疾的常见原因。之前的研究表明，这些情况造成的大脑损伤大多发生在急性侮辱后的几个小时和几天内。这种二次损伤是由初级侮辱引发的炎症引起的。我们相信，通过了解这种继发性炎症是如何发生的，我们将能够确定药物开发的靶点。控制这种继发性炎症的药物可能会限制这些疾病造成的脑损伤。到目前为止，几乎所有涉及活组织的脑损伤研究都集中在动物模型上，不幸的是，几乎没有发现任何与人类直接相关的知识；到目前为止，这些努力还没有出现有效的治疗方法。人们很早就认识到了基于活体人脑进行研究的必要性，但直到最近，获取这种组织几乎是不可能的。在我们医院，我们已经克服了这个问题，建立了一种经伦理批准的程序来捕获过去在脑部手术中不可避免地被牺牲和丢弃的微小脑组织碎片。在急性脑损伤中，受严重影响的患者已被证明受益于使用插入大脑本身的小探头进行侵入性监测。这种探头的插入和移除不可避免地会导致脑部微小碎片的丢失。我们现在能够捕获这种组织用于科学研究，而不是将其丢弃。在这项研究中，我们将把对活体人脑组织的分析与我们在严重脑损伤患者中使用的标准监测的结果结合起来。这项我们首创的技术，测量被称为细胞因子的特殊信号分子。这些蛋白质是免疫细胞用来相互交流的蛋白质。大脑中细胞因子的水平反映了免疫系统各个部分的活动。我们将收集的脑组织将被处理成单独的细胞，并使用一种名为单细胞mRNA测序的技术进行特征分析。因此，这一分析将使我们能够确定损伤后存在哪些细胞，以及哪些细胞正在制造或对我们测量的细胞因子做出反应。因为我们将从每个受试者身上采集两个脑组织样本，所以我们将能够测量脑损伤期间细胞随时间的变化。我们总共将收集20名严重脑损伤患者的样本：我们还将收集接受计划中的神经外科手术的患者的样本，这些患者要么没有任何脑损伤(10名患者)，要么在脑损伤后3个月以上(10名患者)。我们相信，我们的工作将提供对人类大脑炎症的更多了解，这将改变开发安全有效的基于免疫的治疗方法的前景。

Conditions that cause acute brain injury, such as trauma and brain haemorrhage are common causes of death and disability. Previous research has shown that much of the brain damage caused by these conditions occurs in the hours and days after the acute insult. This secondary damage is caused by inflammation that is triggered off by the primary insult. It is our belief that by understanding how this secondary inflammation occurs we will be able to identify targets for drug development. Drugs that control this secondary inflammation can potentially limit the brain damage resulting from these conditions. To date almost all brain injury research involving live tissue has focused on animal models, and unfortunately, little of what was learnt has been found to be directly relevant in humans; to date no effective treatments have emerged from these efforts. The need for research based on live human brain has long been recognised but until recently accessing such tissue was nearly impossible. In our hospital we have overcome this problem by establishing an ethically approved procedure to capture the tiny fragments of brain tissue that in the past where inevitably sacrificed and discarded during brain surgery. In acute brain injury severely affected patients have been shown to benefit from invasive monitoring using a small probe inserted into the brain itself. The insertion, and removal, of this probe involves the unavoidable loss of tiny fragments of brain. We are now able to capture this tissue for scientific research rather than it being thrown away. In this research, we will combine the analysis of this live human brain tissue with the results from the standard monitoring that we use in patients with significant brain injury. This technique, which we have pioneered, measures specialised signalling molecules called cytokines. These are proteins that immune cells use to communicate with each other. The levels of cytokines in the brain reflect the activity of the various parts of the immune system. The brain tissue we will collect will be processed into individual cells and characterised using a technique called single cell mRNA sequencing. This analysis will thus allow us to establish which cells are present after injury and which cells are making or responding to the cytokines we measure. Because we will take two brain tissue samples from each subject we will be able to measure how the cells change over time during brain injury. In total we will collect samples from 20 patients with severe brain injury: we will also collect samples from patients undergoing planned neurosurgery, either without any brain injury (10 patients) or more than 3 months after a brain injury (10 patients). We believe that the increased understanding of human brain inflammation that our work will provide will transform the prospects for developing safe and effective immune based treatments.