糖皮质激素在主动脉夹层血管重构中的调控机制研究.

A portion of aortic dissection (AD) patients die of vessel rupture before definite diagnosis, for this reason the mechanism of vascular remodeling needs to be clarified urgently..Stress has important influence on vascular injury and repair, and glucocorticoids (GCs) play a key role in stress reaction. Supported by the National Natural Science Foundation, our previous studies had confirmed that GCs could rapidly affect the immune and inflammatory response and regulate the contractility of smooth muscle cells. Moreover, we found that the level of serum GCs (cortisol) was significantly higher in AD patients than those in either healthy control or aortic aneurysms. What is the effect of GCs on vascular remodeling in aortic dissection, and what is the regulatory mechanism involved?.Based on the above consideration, we design the research plan as follows:.Firstly, the levels of stress hormones in patients' sera would be detected, and the expression and distribution of their receptors in pathological specimens would be examined as well. Combining the result with clinical data, we would study the significance of abnormal GCs to the development and prognosis of AD. Secondly, the incidence of AD and histopathological changes of aortic samples were examined in the AD model of rat treated by GCs or control, to explore the influence of GCs on aorta vascular remodeling.Thridly, focusing on vascular smooth muscle cells, macrophages and their interaction, we would investigate the regulatory mechanism of GCs in aortic reconstruction..The project may provide new insight into effect of stress on the vascular remodeling, and provide new strategies for early prevention, diagnosis,treatment and prognostic evaluation of AD.

部分主动脉夹层（AD）患者在明确诊断前即因夹层破裂而死亡，其血管重构机制亟待阐明。应激是影响血管损伤修复的重要因素，而糖皮质激素（GCs)是应激反应的枢纽。前期在国家自然科学基金等资助下，我们已证实GCs可快速调节免疫炎症反应，影响平滑肌细胞的收缩，并首次发现AD患者血清皮质醇明显高于对照人群。那么GCs这种应激激素变化对主动脉重构有着怎样的调控机制和意义？本项目拟①检测AD患者血中激素水平，病理标本检测激素受体表达与分布，结合临床资料分析，研究GCs异常对AD发生发展及预后的意义；②在大鼠AD模型上，观察夹层发生情况，测量中膜厚度与管腔直径比值等指标，明确GCs对主动脉血管重构的影响；③体外研究以血管平滑肌细胞和巨噬细胞及其相互作用为着眼点，深入探讨GCs调控主动脉重构的细胞分子机制。本项目将为阐明应激与血管重构的关系提供新的思路，为AD的早期诊断、综合防治及预后评估提出新的靶标和策略。

主动脉夹层病情凶险，起病急骤，很多患者在开始治疗前甚至是明确诊断前即因夹层破裂而死亡。因此，阐明主动脉夹层发病和转归机制对改善夹层预后至关重要。有证据表明血管炎症反应在主动脉血管重构中发挥着重要作用，而糖皮质激素因其强大的抗炎作用被广泛用于临床，那糖皮质激素在主动脉夹层血管重构中有什么作用？本项目分为三个部分：（1）样本研究发现：①主动脉夹层患者血清皮质醇含量明显高于非破裂动脉瘤组和健康对照组；而促肾上腺皮质激素含量未见差异；②三组主动脉中糖皮质激素受体含量也未见差异；③结合临床信息发现主动脉夹层裂口数目与皮质醇含量具有相关性。（2）体内研究发现：①糖皮质激素干预明显降低了小鼠主动脉夹层发生率；②模型组小鼠的主动脉中膜厚度明显高于溶剂对照组，但糖皮质激素干预组和模型组之间无统计学差异；③模型组小鼠主动脉胶原容积分数明显低于溶剂对照组和糖皮质激素干预组。（3）体外研究发现：①糖皮质激素抑制了巨噬细胞分泌基质金属蛋白酶-2，对肿瘤坏死因子-α的分泌具有浓度依赖性；②糖皮质激素减少主动脉平滑肌细胞的迁移，抑制其向分泌型表型转换；③两种细胞共培养抑制了主动脉平滑肌细胞的凋亡，糖皮质激素加强这一效应；④用高通量蛋白微阵列和中和抗体验证的方法筛选出可溶性肿瘤坏死因子II型受体是起作用的关键因子；⑤细胞共培养和糖皮质激素通过影响p38MAPK和HSP27的磷酸化，参与血管重构。本项目首次阐明糖皮质激素参与主动脉血管重构的具体机制，为改善主动脉夹层预后提供了实验数据支撑，有着重大的应用价值和社会意义。