自发性蛛网膜下腔出血后下丘脑神经微环境改变在CIRCI发病中的作用机制

The diagnosis and treatment of critical illness-related corticosteroid deficiency (CIRCI) after spontaneous subarachnoid hemorrhage (sSAH) is challenging and its prognosis is extremely poor, but the underlying mechanism is poorly understood. Besides vasospasm CIRCI might be another factor contributing to a deterioration in the neurological function in the subacute phase of sSAH. In our previous studies, we showed that hypothalamus is a delicate zone in central nervous system. The damaged structure and impaired function of hypothalamic blood-brain-barrier (BBB) could lead to neuronal death, and be closely associated with HPA axis dysfunction and CIRCI incidence. In this project, by using a rat model of sSAH in vivo, BBB model in vitro and clinical observation of sSAH patients, we are further investigating: 1.the evaluation of sSAH severity and prognosis by the degree of HPA axis dysfunction and CIRCI incidence; 2. the relationship between hypothalamic BBB damage, immune-inflammatory response, and glucocorticoids resistance; 3. the significance and mechanism of glucocorticoids receptor sensitization in the treatment BBB damage and HPA axis dysfunction. The objective of this project is to deeply comprehend the pathogenesis of CIRCI and lay the foundation for the diagnosis and treatment of CIRCI after sSAH.

危重症相关皮质类固醇不足（CIRCI）危害大诊治困难，自发性蛛网膜下腔出血（sSAH）后CIRCI可能是脑血管痉挛因素外的另一个亚急性期患者病情进行性加重的重要原因。本课题组近期系列研究（2014JNeurolSci, 2013CritCare）证实：下丘脑是中枢的易损区，该区血脑屏障（BBB）损害所致的病理改变与HPA轴功能紊乱和CIRCI的发病密切相关。本研究将借助体外BBB模型及体内大鼠sSAH模型，进一步研究：1. sSAH后HPA轴功能障碍和CIRCI的发生特征及其与亚急性期神经功能障碍及预后的关系；2.SAH后下丘脑BBB继发性损伤与过度免疫炎症反应及糖皮质激素抵抗的关系及其在CIRCI发生中的意义；3.糖皮质激素受体增敏治疗在调节BBB继发性损伤及HPA轴功能障碍中的作用机制及意义。通过该研究深化对sSAH后CIRCI发病机制的认识，为sSAH后CIRCI的诊治提供基础依据。

危重症相关皮质类固醇不足（CIRCI）危害大诊治困难，自发性蛛网膜下腔出血（sSAH）后CIRCI可能是脑血管痉挛因素外的另一个亚急性期患者病情进行性加重的重要原因。本课题研究在国家自然科学基金的资助下，通过实验动物基础研究，初步探明了sSAH后CIRCI的发病情况及危害，并探索了可能的干预方法，具体研究结果如下：（1）sSAH后血皮质酮呈现先增高，再减低，再升高的变化过程；伤后3-7天是CIRCI发病的高峰期；CIRCI的发生与脑血管痉挛和不良预后密切相关；（2）sSAH后CIRCI的发生与下丘脑BBB结构和功能的破坏，局部微环境的改变和神经细胞内质网应激障碍密切相关；（3）应激剂量糖皮质激素补充、糖皮质激素受体增敏可显著降低CIRCI的发生。上述实验结果已先后发表在：Front Cell Neurosci.，Cell Mol Neurobiol.杂志上。课题负责人参加国内学术会议3次，晋升助理研究员，协助培养硕士研究生2名，并获得所在单位人才孵育基金1项。

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