靶向M1型巨噬细胞MR微成像分析血管外膜炎症在动脉粥样硬化演进中的作用

Recent evidence shows that adventitial inflammation has been suggested to play a initiator in atherosclerosis (AS) progress. Our previous study has demonstrated that the early stage infiltration and activation of macrophages (primarily M1 type) found dispersed throughout the adventitia were responsible for the progress of AS. However, the causal and sequential relationship between M1 macrophage-mediated adventitial inflammation and progression of AS can not be illustrated by the current static methods. So we will dynamically observe and explore the following aspects using M1 macrophage targeted molecular imaging and black-blood dynamic enhanced micro-MR imaging within atherosclerotic lesions in the animal model: 1) the involvement of adventitial M1 macrophage polarization shift in inflamation of adventitia and intima, clarifying their causal and sequential relationship by selectively integer and local intervention; 2) the dynamic dose-effect relationship between adventitial M1 macrophage-initiated neovascularization, permeability transition with inflammatory infiltration and vunerable plaque, clarifying the evovlement rule of inflammatory infiltration and plaque vulnerability. The accomplishment of this project will provide not only a consecutive, dynamic, specific imaging method for examination and assessment of adventitial inflammation and infiltration, but also a judging indicator for AS prognosis and new guidance for its early intervention.

近期研究发现血管外膜炎症可能为动脉粥样硬化（AS）的始发因素。我们前期研究证实AS早期外膜大量巨噬细胞（MΦ，M1型为主）浸润并对AS发展起促进作用。但目前静态的研究方法难以阐释M1型MΦ介导的外膜炎症与AS发生发展的先后、因果关系。本项目拟应用我们已建立的AS模式动物平台，通过靶向M1型MΦ分子影像和“黑血”动态增强MR微成像方法，在体动态观察和研究：1）外膜M1型MΦ的激活与内、外膜炎症的内在联系，整体和局部模型干预明确M1型MΦ在引发内、外膜炎症的时序与因果关系；2）外膜M1型MΦ活化分布与血管新生和斑块易损性的动态变化与量效关系，明确外膜炎症透壁与易损斑块形成的演化规律，阐明血管外膜炎症在AS演进中的作用和地位。本研究将为检测和确切评估血管外膜炎症与透壁演进提供一个连续、动态、特异的影像学方法，为预测AS结局提供风向标和早期干预提供新的理论基础。

近期研究发现血管外膜炎症可能为动脉粥样硬化的始发因素。本项目基于动脉粥样硬化（易损斑块）的动物模型和临床病例基础上，建立了动态监测动脉粥样硬化斑块形态和组织学特征的高分辨率磁共振管壁成像方法（HR-MR-VWI），并完成了影像-病理的验证；优化和建立了分析斑块易损性和透壁炎症的磁共振管壁功能成像（DCE-MRI）药代动力学和纹理分析方法。通过分组对照研究，发现血生化因素（尤其是高水平HbA1c）与血流动力学因素（WSS为代表）对促进动脉粥样斑块易损性和诱发透壁炎症密切相关；通过血管紧张素II（AngII）因素的干预研究，初步明确了巨噬细胞、血管新生与斑块易损性之间的时序和空间关联性，为揭示动脉管壁“由外到内”的透壁炎症机理和风险性评估提供了新的证据和研究思路。