Increased pulmonary vascular permeability is a characteristic feature of lung injury. However, there are no established methods that allow the three-dimensional visualization and quantification of pulmonary vascular permeability in vivo. Evans blue extravasation test and total protein test of bronchoalveolar lavage fluid (BALF) are permeability assays commonly used in research settings. However, they lack the ability to identify the spatial and temporal heterogeneity of endothelial barrier disruption, which is typical in lung injuries. Magnetic resonance (MR) and near-infrared (NIR) imaging have been proposed to image pulmonary permeability, but suffer from limited sensitivity and penetration depth, respectively. In this study, we report the first use of magnetic particle imaging (MPI) to assess pulmonary vascular leakage noninvasively in vivo in mice. A dextran-coated superparamagnetic iron oxide (SPIO), synomag®, was employed as the imaging tracer, and pulmonary SPIO extravasation was imaged and quantified to evaluate the vascular leakage. Animal models of acute lung injury and pulmonary fibrosis (PF) were used to validate the proposed method. MPI sensitively detected the SPIO extravasation in both acutely injured and fibrotic lungs in vivo, which was confirmed by ex vivo imaging and Prussian blue staining. Moreover, 3D MPI illustrated the spatial heterogeneity of vascular leakage, which correlated well with CT findings. Based on the in vivo 3D MPI images, we defined the SPIO extravasation index (SEI) to quantify the vascular leakage. A significant increase in SEI was observed in the injured lungs, in consistent with the results obtained via ex vivo permeability assays. Overall, our results demonstrate that 3D quantitative MPI serves as a useful tool to examine pulmonary vascular integrity in vivo, which shows promise for future clinical translation.

中文翻译：

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首个用于评估急性损伤和纤维化肺体内肺血管渗漏的磁粒子成像

肺血管通透性增加是肺损伤的一个特征。然而，还没有成熟的方法可以对体内肺血管通透性进行三维可视化和量化。伊文思蓝外渗试验和支气管肺泡灌洗液 (BALF) 总蛋白试验是研究环境中常用的渗透性测定方法。然而，他们缺乏识别内皮屏障破坏的空间和时间异质性的能力，这在肺损伤中是典型的。磁共振（MR）和近红外（NIR）成像已被提议用于对肺通透性进行成像，但其灵敏度和穿透深度分别有限。在这项研究中，我们首次使用磁粒子成像（MPI）来无创地评估小鼠体内的肺血管渗漏。采用葡聚糖涂层的超顺磁性氧化铁 (SPIO) synomag® 作为成像示踪剂，对肺部 SPIO 外渗进行成像和量化，以评估血管渗漏。使用急性肺损伤和肺纤维化（PF）的动物模型来验证所提出的方法。MPI 灵敏地检测到体内急性损伤和纤维化肺中 SPIO 外渗，并通过离体成像和普鲁士蓝染色证实。此外，3D MPI 显示了血管渗漏的空间异质性，这与 CT 检查结果密切相关。基于体内 3D MPI 图像，我们定义了 SPIO 外渗指数 (SEI) 来量化血管渗漏。在受伤的肺部观察到 SEI 显着增加，这与通过离体渗透性测定获得的结果一致。总的来说，我们的结果表明，3D 定量 MPI 是检查体内肺血管完整性的有用工具，这为未来的临床转化带来了希望。