靶向单核/巨噬细胞对主动脉夹层的防治作用和机理研究

Aortic dissection (AD) is a devastating disease characterized with dormant onset, rapid progress and high mortality rate. At present stage, neither the clinical nor the basic research revealed the cause of aortic rupture. Identification the mechanism will not only provide the target for the prevention, but also for the treatment. Our previous study showed that the inflammatory response was closely related to the occurrence of AD (Int J Cardiol. 2013；168: 3065-6).To reveal the causal relationship between AD and inflammation, two study systems including chronic AD and acute AD were setup. Here, we show that inflammatory cells, especially macrophages as the major population, were only detected in the mice developed AD, while not in the mice without AD. Monocyte/macrophage depletion in LysMiDTR mice, significantly reduced AD incidence and abrogated the characteristics of AD including maximum thickness of aortic wall and elastin fragmentation. The following research will be carried out based on the previous results. ① Multiple strategies will be used to further confirm the initiation effect of monocytes/macrophages on AD; ② Identification of the original source of macrophages infiltrated in the rupture site of AD; ③ Regulation mechanism on mobility of macrophage. This project will deepen the understanding of the AD pathogenesis and further provide the intervention targets on AD.

主动脉夹层（AD）是一种发病隐匿、进展迅猛并且死亡率极高的大血管病。目前，临床和基础研究都未揭示触发主动脉撕裂的原因，申请团队前期的研究显示炎症反应与AD发生密切相关。为了揭示AD发生与炎症反应的因果关系，申请团队分别建立急性和慢性两个研究体系，发现巨噬细胞在血管撕裂位置的浸润显著高于T淋巴细胞和中性粒细胞。随后申请团队利用特异性敲除单核/巨噬细胞的LysMiDTR小鼠,并首次发现敲除单核/巨噬细胞的小鼠基本不发生AD，提示单核/巨噬细胞在启动AD发生方面扮演重要角色。基于前期研究基础,本项目开展以下工作：①采用多种研究策略继续确认单核/巨噬细胞在启动AD发生方面的作用；②明确浸润主动脉撕裂部位的巨噬细胞是来源于循环单核细胞, 还是来源于血管定居巨噬细胞的问题；③开展外周血来源巨噬细胞或血管定居巨噬细胞在AD进程的调控机理研究。本项目的实施将深化AD的发病机理研究，为AD防治提供干预靶点。

申请团队在建立急性和慢性AD的研究体系之后，明确了巨噬细胞在血管撕裂位置的浸润显著高于T淋巴细胞和中性粒细胞。申请团队随后利用特异性敲除单核/巨噬细胞的LysMiDTR小鼠,揭示敲除单核/巨噬细胞显著降低AD发生率，提示单核/巨噬细胞在启动AD发生方面扮演重要角色，上述研究结果发表在Life Sciences上 (Life Sci. 2020; 254:116927)。为了明确浸润主动脉撕裂部位的巨噬细胞是来源于循环单核细胞,还是来源于血管定居巨噬细胞的问题，申请团队构建LysMiDTR/LysMiDTR、LysMDT/LysMiDTR等多种类型嵌合鼠考察白喉毒素（DT），血管紧张素(AngII)干预与不干预条件下对AD发生的影响，从而明确血管固有巨噬细胞在AD发生发展中的关键作用。在明确了血管巨噬细胞的重要作用之后，申请团队与制剂团队合作，开展靶向巨噬细胞的治疗研究，研究成果发表在J Control Release（J Control Release. 2021;337:224-235）上。在本项目的资助下，项目负责人作为通讯作者共发表相关SCI研究论文4篇 （Targeted depletion of monocyte/macrophage suppresses aortic dissection with the spatial regulation of MMP-9 in the aorta. Life Sci. 2020; 254:116927.；Macrophage-biomimetic anti-inflammatory liposomes for homing and treating of aortic dissection. J Control Release. 2021 Sep 10;337:224-235.；Progression and Regression of Abdominal Aortic Aneurysms in Mice. Curr Med Sci. 2021 Oct;41(5):901-908.；Rosmarinic acid suppresses abdominal aortic aneurysm progression in apolipoprotein E-deficient mice. Planta Med. 2021