蛛网膜下腔出血后铁超载所引起脑损伤的病理生理研究

The mortality rate following subarachnoid hemorrhage (SAH) is still 45%;the morbidity is also very high. Thus, brain injury represents the primary cause of poor outcome in SAH patients.Our previous studies have indicated that iron overload contributes significantly to brain damage after intracerebral hemorrhage. Deferoxamine, an irion chelater, can be used to relive the brain damage.Following SAH, iron overload occurs after erythrocyte lysis. However, it is unknown whether iron overload are involved in the brain damage after SAH.This study is to evaluate the brain injury quantitatively and quanlitatively at each time point after subarachnoid hemorrhage on rat SAH model to explore the potential pathophysiologic mechanism of iron overload contributing to brain damage. Based on the heme to iron degeneration process, iron-chelater is adopted to relieve brain injury and improve the prognosis of subarachnoid hemorrhage.Therefore, it will provide a theretical basis and practical guidance for intervention for brain damage after SAH.

SAH的死亡率高达45%左右，且有高的致残率。脑损伤是其不良预后的重要原因。但造成SAH后脑损伤的机制目前仍不明确。我们前期研究证明脑实质出血后造成细胞铁超载，形成严重的脑损伤。铁螯合剂Deferoxamine可减轻这种损伤。SAH后红细胞在蛛网膜下腔裂解同样可造成铁超载，但SAH后的铁超载是否参与脑损伤目前尚无相关报道。本课题利用大鼠蛛网膜下腔出血模型对蛛网膜下腔出血后各时间点的铁超载与脑损伤之间做出定量和定性测定，分析SAH后铁超载造成脑损伤的病理生理过程，并依据血红蛋白至铁的代谢途径，进行干预铁超载以减轻脑损伤。从而，为SAH后脑损伤的干预提供理论基础和实践指导

根据本课题研究计划书，通过颈内动脉分叉部穿刺法成功建立大鼠蛛网膜下腔出血模型并在此基础上进一步成功建立野生型小鼠及转基因小鼠的蛛网膜下腔出血模型。针对不同时间点的蛛网膜下腔出血模型进行增强Perl’s 染色及铁蛋白免疫组化染色成功测定脑组织各类相关蛋白水平。通过免疫组化染色及Western blot证实SAH后存在铁超载，铁超载在SAH急性期引起脑水肿、神经元死亡、白质损伤、血脑屏障损伤、脑积水等，使用铁螯合剂去铁敏可抑制铁相关蛋白的表达继而减少SAH后铁超载引起的脑损伤。同时研究发现脂质转运蛋白-2(Lipocalin 2, LCN2)参与了铁超载引起脑损伤的病理生理过程。SAH急性期可引起小鼠白质损伤，白质损伤区域内LCN2表达显著提高，LCN2敲除可缓解脑白质损伤。