miR-17对主动脉管壁炎症反应的调控及机制研究

With rapid progress of Endovascular stent-graft repair for the treatment ofdescending aortic dilation diseases as an important alternative to conventional opensurgery, the postoperative adverse events caused by stent-grafts were mounting anddisturbing. Stent graft-induced new entry is one of the most devastating complications and may cause either aneurysmal dilation or rupture with high mortality. However, there were few study on the underlying mechanical and biological mechanisms. Neither means for prevention nor methods for intervention.were proposed for these complications. As an alien objective, the endograft cannot fully conform to the host arterial tissues and mechanical stress may concentrated over the contact region. Moreover, after being deployed it can induce inflammatory response. The aims of this study is to quantitatively analyze the inflammatory response caused by stent-graft and to treat it with a new kind of high conformable mir-17-loaded anti-inflammatory stent-graft. This study will be conducted in two aspects: First, to establish aortic dissection model in large animal and to explore mechanism of inflammation induced by the interaction between graft and aortic wall ; Second, design a new endograft with help of computer-assisted design and fabricate it with 3D printing and covered with electro-spinned mir-17-loaded membrane that can be biological therapeutic to regulate local inflammatory; use it on the animal model of aortic wall inflammation to test and analyze the therapeutic effects and underlying mechanism. This study will provide important in-sight on the mechanism of stent graft-induced aortic wall inflammation and relationship between post-operative adverse events. It can offer an important way to design new concept of stent-graft to preferably match the aortic dissection configuration and with biological therapeutic ability. As biomechanical rationales of endovascular treatment of aortic dissection, the outcomes of this study may have great clinical potential.

主动脉扩张病易破裂致死，病情凶险。血管腔内隔绝术可实现对该疾病的快速微创治疗，但术后再发破裂等不良事件严重阻碍这一新技术的发展。我们前期研究发现：腔内移植物与主动脉管壁的不匹配及相互作用产生炎症反应是关键的影响因素，具体机制、预防和干预的方法亟需研究。本项目拟①制造移植物与管壁相互作用诱发管壁炎症的大动物模型，探索炎症发生机制；②以巨噬细胞和血管平滑肌细胞及其相互作用为着眼点，研究mir-17及IL-6等对炎症参与主动脉血管重构的调控机制。本研究结果将有助于阐明主动脉腔内隔绝术后不良事件发生的炎症相关细胞分子机制，将可能为主动脉疾病的治疗提供新的思路和策略。

主动脉夹层病情凶险，腔内治疗因微创、安全且有效而广泛开展，但术后逆撕、远端扩张和再发破裂等不良事件严重影响预后，其有效的治疗方案亟待研究。我们前期发现腔内治疗后支架与管壁相互作用可以导致炎症且与不良事件发生密切相关。支架移植物所引起的炎症反应是主动脉夹层病变区不良主动脉重塑的独立危险因素。本项目通过同轴静电纺织技术，将药物甲强龙(methylprednisolone, MPSS) 负载于支架移植物，构建出新型载药控释腔内支架移植物，并探索其释放特点及有效浓度范围。构建家猪主动脉夹层模型进行分组，使用不同的腔内移植物进行主动脉腔内治疗，通过影像学（CTA、PET-CT等）指标和生物样本检测，分析炎症反应的时相特征及其对管壁重塑的影响，研究炎症反应影响主动脉血管重构的效应及调控管壁炎症的方法。.申请人使用同轴静电纺织技术，制造出甲强龙为核心层、聚L-丙交酯-己内酯为壳层的纳米纤维，并将其负载于主动脉支架，从而构建出新型载药支架移植物，通过体外实验和动物实验验证了其有效的药物体外控释并在体内精准调控管壁炎症：①纳米纤维直径在15-20um之间时的强度高于其他大小直径；②MPSS累及释放比例在第1、1.25天迅速升高，载药量为1.0 mg的覆膜释放比例30天后可达86.4%，；③体内实验结果显示，TEVAR术后3、6、9、12、15、30天非载药移植物腔内干预组CRP、IL-6和TNF-α含量明显高于新型载药移植物腔内治疗组；④术后7天行PET-CT，新型载药移植物腔内治疗组TBR值显著低于夹层建模组以及非载药移植物腔内治疗组(P＜0.001)；⑤新型载药主动脉移植物能明显抑制CD68阳性细胞、MPO阳性细胞等炎症细胞在管壁中的聚集，降低全身炎症反应，有效促进局部管壁的修复重塑。本研究所获信息，将为主动脉夹层腔内微创治疗术后炎症相关问题提供重要的科学数据，将为研究主动脉血管重构过程提供新的干预途径和思路，将为进一步提高主动脉夹层腔内治疗的水平提供新的策略。