Molecular Magnetic Resonance Imaging of Inflammation

项目摘要/摘要 非酒精性脂肪性肝病(NAFLD)影响着8000万至1亿美国公民。最常见的形式 非酒精性脂肪肝(NAFL)是一种良性和非进行性的疾病。然而，~20% 的NALFD病例被归类为非酒精性脂肪性肝炎(NASH)，这是一种炎症性疾病， 通常进展为肝纤维化、肝硬变，最后发展为肝功能衰竭或肝癌。唯一的办法就是 NAFL与NASH的区别是通过有创活检，这是昂贵的，构成了不可忽视的严重风险 内出血，因此不适合患者随访。活组织检查不是一种实用的筛查工具，而是作为一种 结果NASH一般在病情进展到晚期才被确诊。对生存有好处的是 预计在未来几年内将进行早期诊断和一些NASH疗法。非侵入性 迫切需要诊断NASH或监测治疗反应的方法。曾经有过 晚期纤维化和肝硬变的放射学诊断进展，但目前还没有方法对 总是先于疾病进展的肝脏炎症。 髓过氧化物酶(MPO)是一种潜在的鉴别诊断NASH的影像生物标志物。MPO是分泌出来的 通过激活的中性粒细胞作为炎症微环境的一部分，并转化为活性氧物种 (ROS)由中性粒细胞呼吸生成具有高度伤害性的ROS，如高氯酸。MPO具有很高的 在发炎的肝脏细胞外空间中大量存在，但在健康组织中很少。 我们最近开发了一种小分子铁基磁共振造影剂(Fe-PyC3A)，它可以进行10倍的 在ROS存在的情况下，弛豫度(MR信号产生能力)增加。史无前例的大 弛豫度的变化是通过Fe2+氧化成Fe3+来实现的。Fe2+离子是一种非常低效的弛豫剂，但 高自旋Fe3+是一种非常有效的弛豫剂。急性胰腺炎小鼠模型的初步成像实验 胰腺炎显示Fe-PyC3A对健康组织的对比度增强很少或没有，但很强 以及急性炎症组织的选择性对比剂增强。重要的是，对比度增强的水平 与体外实验室定量测定的MPO活性水平呈显著正相关(r= 0.95，P&lt；0.0001)。 这项建议侧重于优化和验证氧化还原活性铁络合物作为MPO特异性对比 肝脏核磁共振试剂。这项研究的最终目标是一种非侵入性的成像测试，以区分患者 来自患者的非进展性NAFL患者将受益于有创活检。的直接输出 拟议的工作将是一种MRI造影剂，该造影剂1)专用于急性炎症，2)可以区分炎症 与小鼠非炎症性脂肪肝相比，以及3)没有临床前安全信号。

Project Abstract/ Summary Non-alcoholic fatty liver disease (NAFLD) affects between 80 to 100 million US citizens. The most common form of the disease is a benign and non-progressive condition called non-alcoholic fatty liver (NAFL). However, ~20% of NALFD cases are classified as non-alcoholic steatohepatitis (NASH), an inflammatory condition that commonly progresses to liver fibrosis, cirrhosis, and finally to liver failure or liver cancer. The only way to differentiate NAFL from NASH is via invasive biopsy which is expensive, poses a non-negligible risk of serious internal bleeding, and is thus ill-suited for patient follow-up. Biopsy is not a practical screening tool and as a result NASH typically goes undiagnosed until progression to advanced disease. There is a survival benefit to early diagnosis and a number of NASH therapeutics are anticipated within the next few years. Non-invasive methods to either diagnose NASH, or to monitor treatment response are sorely needed. There have been advances toward radiologic diagnosis of advanced fibrosis and cirrhosis but there are no methods to image the liver inflammation that invariantly precedes disease progression. Myeloperoxidase (MPO) is a potential imaging biomarker for differential diagnosis of NASH. MPO is secreted by activated neutrophils as part of the inflammatory microenvironment and converts reactive oxygen species (ROS) generated by neutrophil respiration into highly injurious ROS like perchlorous acid. MPO is highly abundant in the extracellular space of inflamed liver, but is scarce in healthy tissue. We recently developed a small molecule Fe-based MRI contrast agent (Fe-PyC3A) that undergoes a 10-fold increase in relaxivity (MR signal generating potency) in the presence of ROS. This unprecedentedly large relaxivity change is achieved by oxidation of Fe2+ to Fe3+. The Fe2+ ion is a very inefficient relaxation agent but high-spin Fe3+ is a very potent relaxation agent. Preliminary imaging experiments using a mouse model of acute pancreatitis demonstrate that Fe-PyC3A provides little-to-no contrast enhancement of healthy tissue but strong and selective contrast-enhancement of acutely inflamed tissue. Importantly, the level of contrast enhancement correlates significantly and positively with MPO activity levels determined by ex vivo laboratory quantitation (r = 0.95, P < 0.0001). This proposal focuses on optimizing and validating redox active Fe complexes as MPO-specific contrast agents for liver MRI. The ultimate goal of this research is a non-invasive imaging test to differentiate patients with non-progressive NAFL from patients will benefit from invasive biopsy. The immediate outputs of the proposed work will be an MRI contrast agent that is 1) specific to acute inflammation, 2) can differentiate inflamed vs. non-inflamed fatty liver in mice, and 3) does not exhibit pre-clinical safety signals.