脑铁含量对脑梗死静脉溶栓出血转化促发作用及机制研究

Hemorrhagic transformation is part of the natural history of ischemic infarction, and can also be precipitated or enhanced by therapeutic interventions of ischemic stroke. The fear of hemorrhagic transformation and its associated complications hinders the widespread use of reperfusion therapy in acute ischemic stroke. This project aims to deepen our understanding of brain iron mechanisms for thrombolysis related hemorrhagic transformation, and identifying individuals at high risk for hemorrhagic transformation for safer and better use of thrombolysis of ischemic stroke. We propose to use brain MRI and/or CT to estimate iron deposition in the brain and ischemic tissue of patients with acute ischemic stroke who received IV tPA, and to examine the relationship between MRI/CT estimates of brain iron and thrombolysis related hemorrhagic transformation and long-term outcomes; and then to develop the optimal predictive model integrating biomarkers with clinical and imaging factors to identify high risk individuals of thrombolysis related hemorrhagic transformation following ischemic stroke. We will then testify Fe²ᐩ-mediating MMP-9 through HMGB1 pathways is one of the key mechanisms that destroys the blood-brain barrier and causes hemorrhagic transformation in animal studies. This project could lead to the development of potential approaches to reduce the risk of hemorrhagic transformation by inhibiting or blocking of the above pathways, and to aid the selection of patients at low risk of hemorrhagic transformation for more widespread use of reperfusion therapy.

脑梗死静脉溶栓出血转化发生率高，可加重病情及增加死亡风险。目前其确切机制尚不清楚，缺乏有效预测手段。已有少量基础与临床研究提示铁可能在脑梗死后溶栓治疗相关出血转化中起重要促发作用，但缺乏脑铁含量与出血转化的直接研究证据；且如何测定脑铁含量是提供直接证据、解决问题的关键。本课题组依托前期脑梗死出血转化生物标志物研究经验，借助国际合作单位哈佛医学院脑铁含量测定技术优势，拟前瞻性收集静脉溶栓的脑梗死患者并采集基底节T2 SI和/或CT HU数据，率先探讨CT测定脑铁含量可行性，分析证实基底节T2 SI和/或CT HU可以预测脑梗死后溶栓相关出血转化的发生；进一步行动物实验验证Fe²ᐩ通过调控HMGB1促进MMP-9表达和血脑屏障破坏导致出血转化是其关键分子机制；以期为脑铁含量过多导致脑梗死静脉溶栓出血转化发生提供直接证据并揭示机制为防治出血转化提供潜在干预靶点。

出血转化（Hemorrhagic transformation，HT）是脑梗死患者静脉溶栓治疗常见并发症之一，研究提示脑铁含量可能导致脑梗死后HT发生、是预测和防治HT的潜在靶点。本项目围绕脑铁含量对HT的影响和机制问题，首先利用华西医院队列和外部队列，分别分析基底节电子计算机断层扫描（CT）放射不透性（HU）和磁共振（MRI）T2加权相信号强度（T2 SI）来间接估计脑铁含量，并分析梗死对侧（健侧）半球基底节HU或T2 SI值与接受静脉溶栓治疗的急性脑梗死患者发生HT的相关性，发现健侧基底节相对HU值和相对T2 SI值与HT均未见显著的相关性。分析阴性结果可能与以下因素有关：通过CT或MRI常规序列评估基底节铁含量相对粗糙，采用高级MRI序列如定量磁化率图/定量磁敏感图（quantitative susceptibility mapping, QSM）可能更精准。课题组针对这个问题进行了改进：纳入患者行MRI QSM检查，测定健侧基底节磁化率值，分析其与HT的关系。同时，通过临床研究发现血清铁蛋白和高铁蛋白血症均与伴高血糖的脑梗死患者HT独立相关。课题组进一步构建高血糖大鼠大脑中动脉闭塞（MCAO）模型探索铁超载加重HT的机制，发现在伴高血糖急性脑缺血大鼠中急性铁超载加重BBB损伤从而导致HT。研究结果有助于揭示HT的影响因素和潜在机制，可为防治脑梗死后HT提供科学依据、从而提高静脉溶栓治疗率和安全性及改善患者预后。