响应MPO的MR分子成像评估COPD早期心肌损伤及抗氧化治疗效果的实验研究

The most common complication of chronic obstructive pulmonary disease (COPD) is cardiovascular pathologic disorder. Oxidative stress and release of active oxygen species play an important role in myocardial injury resulting from COPD. As an important marker of inflammatory reaction, the activity of myeloperoxidase (MPO) is closely related to oxidative stress and myocardial injury. This program aims at the development of magnetic resonance molecular probe targeted to activity of MPO (named Gd-DOTA-ED) in tissue. The molecular probe will be developed by labeling 5-hydroxytryptamide (“sensing” the activity of MPO). For this labeling, 5-hydroxytryptamide, tyrosine and dioxyphenylalanine act as the structural unit of the electronic donor, and Gd-DOTA is the magnetic resonance contrast agent. The vitro study will be performed to confirm that this probe has favorable biocompatibility and targeting specificity. The vivo study will be performed with the previous magnetic resonance molecular imaging of myocardium to illustrate myocardial injury resulting from COPD in a miniature pig mode to detect the level of active oxygen species and the status of oxidative stress of myocardium, finally to clarify the possibility of detecting early myocardial injury. Subsequently, the effect of antioxidant therapy of myocardial injury due to COPD will be investigated by the above-mentioned molecular imaging in combination with the myocardial microcirculation change and the degree of myocardial fibrosis as demonstrated on cardiac magnetic resonance multimodality imaging. This research proposal may be potential to establish new strategies and methods for noninvasively investigating and early treatment in COPD early myocardial injury. The relevant research findings in our program will be expected to provide a new idea and methodological basis for the noninvasive evaluation of early myocardial injury resulting from COPD and timely intervention of the myocardial disorder.

慢性阻塞性肺疾病(COPD)最主要并发症是心血管损伤，机体氧化应激及活性氧释放在COPD心肌损伤中扮演重要角色。髓过氧化物酶(MPO)是炎症反应的重要标记物，其活性与氧化应激及心肌损伤关系密切。本项目选择血清素作为MPO响应分子，并与酪氨酸、多巴共同作为电子供体结构单元，以Gd-DOTA作为MR信号组件，拟制备高度响应组织内MPO活性MR分子探针(Gd-DOTA-ED)，并研究该探针的弛豫度。用体外实验证明该探针具有良好的生物相容性及响应特异性。利用中华小型猪COPD模型开展心脏MR分子成像，旨在检测COPD心肌组织的活性氧水平及氧化应激状态，阐明该探针诊断COPD早期心肌损伤的可行性；以前述分子成像为基础，联合心脏MRI多模态显像，从心肌微循环改变、心肌纤维化程度角度研究COPD心肌损伤抗氧化治疗效果。相关研究成果可望为无创评价、及时干预COPD早期心肌损伤提供新思路和方法学基础。

COPD心肌损伤是引起患者死亡的主要原因，早诊早治具有重要的临床意义。本项目旨在研究相应型MPO分子探针从代谢角度监测心肌应激状态，并结合多模态CMR成像观察不同COPD造模时期心肌的形态、功能、组织学及微观功能的改变，从而多维度，多角度实现COPD早期心肌损伤的综合评估。本项目成功构建了COPD小型猪模型，通过利用响应型MPO分子探针及多模态心脏磁共振检查，结合组织病理学结果，证实了COPD小型猪可在心脏未发生形态学及组织学改变的情况下，早期即可发生心肌氧化应激的异常及微观结构的改变，可用于早期无创观察COPD心肌改变，从而为早期诊断、早期干预提供支持。在COPD心肌损伤的临床研究方面，我们还发现基于CMR-FT测定的心肌应变，特别是纵向PS，可早期定量评价LVEF正常且未合并肺动脉高压的COPD患者左心室心肌亚临床功能障碍，有望为临床诊断COPD心肌损伤提供影像学依据。