乙酰硫酸肝素在急性A型主动脉夹层全身炎症反应中的始动作用及机制研究

The clinical progression and laboratory findings of the acute type A aortic dissection (AAAD) resemble the vicious circle presented in patients with severe acute pancreatitis (SAP), namely “Inflammation→Systemic inflammatory response syndrome (SIRS) → Multiple organ dysfunction syndrome (MODS) →Death”. More recently, heparan sulfate (HS) has been recognized as an important mediator in triggering the excessive production of inflammatory molecules in the development of SAP, potentially through a Toll like receptor 4 (TLR4)-dependent pathway. Previous studies have detected high expression of HS protein in intimal and medial layers of the aortic wall, and also demonstrated a marked increase of HS level in serum at the onset of aortic dissection. With regard to the pro-inflammatory role of HS, we hypothesize that HS might actively participate in the process of SIRS and subsequent MOF in the setting of AAAD. Therefore, in the present study, with the aid of intravascular ultrasound, digital simulation, gene silencing and flow cytometry, a well-established murine model and inflammatory cells culturing are used to investigate the functional role and underlying mechanisms of HS in the pathogenesis of SIRS induced by AAAD. This study may open new horizons in therapeutic strategies aiming at blocking the progression of SIRS and MOF and decreasing the risk of aortic rupture in the setting of AAAD, and also may provide novel evidence for optimatizing the timing of surgical interventions.

急性A型主动脉夹层（AAAD）的临床发展过程和实验室发现与重症急性胰腺炎（SAP）极为相似，表现为“炎症反应→SIRS→MODS→死亡”。最新研究证实硫酸乙酰肝素（HS）通过TLR4途径激活固有免疫系统，释放大量炎症介质并引发SIRS，是SAP炎症反应的扳机点。HS广泛存在于主动脉壁的内膜和中膜内层。本团队前期发现：AAAD剥离伊始，即有大量HS释放入血。鉴于HS在SAP所致SIRS中的扳机作用，本项目拟在前期标准化动物模型基础上，结合炎症细胞培养模型，采用术中血管超声、数字模拟、基因沉默和流式细胞等技术，揭示HS在AAAD所致SIRS中的作用及其依赖的细胞途径，以及围绕HS的药物干预对炎症反应的改善情况，求证HS在AAAD全身炎症反应中的扳机作用和机制。有望为控制AAAD中SIRS的进展，预防MODS发生及主动脉破裂，优化手术时机提供新的理论基础，为有效防治提供新思路和新靶点。

本研究利用标准化犬急性主动脉夹层（AAAD）模型，采用真/假腔同时、分别采血的方法在夹层进展过程中多时点检测真/假腔血液中硫酸乙酰肝素（HS）、炎症因子以及炎症细胞激活程度，并比较其差异。进一步在细胞模型中探讨HS对单核巨噬细胞系统刺激炎症因子释放的影响和机制，以及H210药物是否通过上述机制发挥干预HS激活单核巨噬细胞系统释放炎症因子的作用。本研究结果显示假腔中的HS水平、炎症因子水平以及炎症细胞激活水平逐渐高于真腔， HS释放增多可能引起主动脉夹层全身炎症反应，且HS可能是通过单核巨噬系统激活全身炎症反应。进一步，HS激活单核巨噬细胞系统可能是通过TLR4、NF-κB、IRF-3、p38 MAPK通路实现的，且这一过程在细胞和全身反应层面可被H210药物抑制。