Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin.
Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.
Am J Physiol Lung Cell Mol Physiol. 2021 Mar 1;320(3):L436-L450. doi: 10.1152/ajplung.00066.2020. Epub 2021 Jan 6.
To develop a dynamic in vivo near-infrared (NIR) fluorescence imaging assay to quantify sequential changes in lung vascular permeability-surface area product (PS) in rodents. Dynamic NIR imaging methods for determining lung vascular permeability-surface area product were developed and tested on non-irradiated and 13 Gy irradiated rats with/without treatment with lisinopril, a radiation mitigator. A physiologically-based pharmacokinetic (PBPK) model of indocyanine green (ICG) pulmonary disposition was applied to in vivo imaging data and PS was estimated. In vivo results were validated by five accepted assays: ex vivo perfused lung imaging, endothelial filtration coefficient (K) measurement, pulmonary vascular resistance measurement, Evan's blue dye uptake, and histopathology. A PBPK model-derived measure of lung vascular permeability-surface area product increased from 2.60 ± 0.40 [CL: 2.42-2.78] mL/min in the non-irradiated group to 6.94 ± 8.25 [CL: 3.56-10.31] mL/min in 13 Gy group after 42 days. Lisinopril treatment lowered PS in the 13 Gy group to 4.76 ± 6.17 [CL: 2.12-7.40] mL/min. A much higher up to 5× change in PS values was observed in rats exhibiting severe radiation injury. Ex vivo K (mL/min/cm HO/g dry lung weight), a measure of pulmonary vascular permeability, showed similar trends in lungs of irradiated rats (0.164 ± 0.081 [CL: 0.11-0.22]) as compared to non-irradiated controls (0.022 ± 0.003 [CL: 0.019-0.025]), with reduction to 0.070 ± 0.035 [CL: 0.045-0.096] for irradiated rats treated with lisinopril. Similar trends were observed for ex vivo pulmonary vascular resistance, Evan's blue uptake, and histopathology. Our results suggest that whole body dynamic NIR fluorescence imaging can replace current assays, which are all terminal. The imaging accurately tracks changes in PS and changes in lung interstitial transport in vivo in response to radiation injury.
为了开发一种用于定量研究啮齿动物肺部血管通透性表面积产物（PS）的动态活体近红外（NIR）荧光成像分析方法。开发了用于确定肺部血管通透性表面积产物的动态 NIR 成像方法，并在未接受辐射和接受 13Gy 辐射的大鼠以及接受雷米普利（一种辐射缓解剂）治疗的大鼠中进行了测试。应用基于生理学的药代动力学（PBPK）模型对吲哚菁绿（ICG）肺分布的体内成像数据进行了分析，并估计了 PS。体内结果通过五种公认的方法进行了验证：离体灌注肺成像、内皮滤过系数（K）测量、肺血管阻力测量、伊文思蓝染料摄取和组织病理学。PBPK 模型衍生的 PS 增加了 42 天后从非照射组的 2.60±0.40[CL：2.42-2.78]mL/min 增加到 13Gy 组的 6.94±8.25[CL：3.56-10.31]mL/min。雷米普利治疗将 13Gy 组的 PS 降低至 4.76±6.17[CL：2.12-7.40]mL/min。在表现出严重辐射损伤的大鼠中，PS 值的变化高达 5 倍。离体 K（mL/min/cm HO/g 干肺重），一种肺血管通透性的测量方法，在照射大鼠的肺部显示出与非照射对照相似的趋势（0.164±0.081[CL：0.11-0.22]），而接受雷米普利治疗的照射大鼠则降低至 0.070±0.035[CL：0.045-0.096]。离体肺血管阻力、伊文思蓝摄取和组织病理学也显示出相似的趋势。我们的结果表明，全身动态 NIR 荧光成像可以替代所有终末方法。该成像方法可以准确地跟踪 PS 的变化和辐射损伤后体内肺间质转运的变化。
