血小板激活对急性A型主动脉夹层全身炎症反应和血管生物力学性能的影响及机制研究

Acute type A aortic dissection (AAAD) is emergency and severe disease of cardiac surgery department and the main treatment of AAAD is surgery. Aorta rupture before surgery and hemorrhage during operation were associated with degradation of vascular biomechanical properties which caused poor prognosis. Previous study found close relationship of vascular biomechanical properties and inflammation which may caused by the activation of platelet. With regard to the pro-inflammatory role of platelet activation, we hypothesize that platelet activation might actively participate in the process of inflammatory reaction and subsequent degradation of vascular biomechanical properties in the setting of AAAD. Therefore, in the present study, with the aid of ultrasound, flow cytometry, PCR and ELISA, a well-established canine model and platelet activation in vitro are used to investigate the functional role and underlying mechanisms of platelet activation in the pathogenesis of inflammatory reaction induced by AAAD and its influence to biomechanical properties. The study may open new horizons in therapeutic strategies aiming at blocking the inflammation, increasing vascular biomechanical properties and then improving prognosis of AAAD patients.

急性A型主动脉夹层（AAAD）是心脏外科的危急重症，手术治疗是AAAD的主要治疗方案。术前夹层破裂和术中吻合口出血严重影响患者预后，并且与血管生物力学性能下降有关。本团队前期研究发现AAAD血管生物力学性能下降与全身炎症反应出现具有密切联系，而血小板激活可能参与全身炎症反应的产生。本项目拟在前期标准化动物模型的基础上，结合血小板体外激活实验，采用术中超声、流式细胞、PCR、ELISA等关键技术，揭示血小板激活在全身炎症反应中的始动作用，以及炎症反应对血管力学性能的影响。本研究有望为减轻AAAD术前炎症反应、提高夹层血管力学性能，进而改善患者预后提供新的治疗思路和新靶点。

急性A型主动脉夹层（type A Stanford Acute Aortic Dissection, AAAD）是心脏大血管外科的危急重症，积极手术仍是目前治疗AAAD的主要方案，但也有部分病人因无法及时接受手术而出现术前死亡，主动脉夹层破裂是AAAD患者术前死亡的主要原因之一；随着医疗技术的进步，AAAD手术效果逐渐改善；但即使如此，AAAD的外科手术死亡率仍高达25%。术中由于血管水肿、组织松脆导致的吻合口出血仍是AAAD外科手术的难点之一。术前夹层破裂和术中吻合口易出血均可能与AAAD血管组织力学性能下降有关。本项目通过建立犬主动脉夹层动物模型，通过检测不同时间点血小板、中性粒细胞、单核细胞、淋巴细胞激活水平变化趋势，mtDNA释放和炎症因子水平变化规律，以及血管壁力学性能，发现主动脉夹层发生后先出现血小板激活以及mtDNA释放，继而引起全身炎症反应，导致血管力学性能下降；通过建立体外血小板激活模型发现主动脉夹层全身炎症反应的机制可能是主动脉中膜与血液接触，激活血小板后通过NADPH/ROS/MPTP/MDA过程释放mtDNA，mtDNA作为致炎因子引起全身炎症反应；在体内和体外模型中，抗血小板激活剂Tirofiban可能通过抑制血小板激活及其后续机制，在动物和细胞水平减轻炎症反应，最终达到保护主动脉夹层血管力学性能的目的，为临床药物治疗主动脉夹层提供了新的思路和理论依据。