Impact of hepatic perfusion on lobular and lobar distribution of test compound metabolism in rats

肝灌注对大鼠试验化合物代谢的小叶和脑叶分布的影响

• 批准号: 447296368
• 负责人: Professorin Dr. Uta Dahmen
• 金额: --
• 依托单位: Klinik für Allgemein-, Viszeral- und Gefäßchirurgie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/447296368?language=en
• 关键词: Impact; hepatic; perfusion; lobular; lobar

Patients subjected to extended liver resection ((e)PHx) have a high risk to experience postoperative liver dysfunction or even liver failure, especially in case of preexisting liver disease. Our research group QuaLiPerF aims to enhance the understanding of the quantitative and spatial relationship between hepatic perfusion and function in healthy, steatotic and regenerating livers after surgery using a systems medicine approach. This project will focus on assessing the impact of perfusion perturbation and perfusion impairment on loss and recovery of liver function. We hypothesize that spatial inhomogeneity of perfusion matches the functional performance of the hepatocytes and their proliferation during regeneration. It is our aim to assess the impact of hepatic perfusion on test compound metabolism in normal, steatotic and regenerating livers by a) spatially resolved quantification of hepatic perfusion and steatosis on the lobular and lobar scale,b) exploring the capacity and spatial distribution of test compound metabolism in relation to hepatocyte proliferation.To reach this goal, we are going to investigate liver perfusion impairments on multiple scales using three different approaches of perfusion perturbation in the rat model: hepatic steatosis, portal vein ligation, and liver resection. Animals will be subjected to detailed assessment of hepatic hemodynamics and microcirculation using side-stream dark field imaging and an optical sensor revealing the tissue oxygenation. Probing multiple liver lobes will reveal the heterogeneity of hepatic perfusion.Test compound metabolism is used for scale spanning assessment of hepatic function. We will perform pharmacokinetic studies after applying five different test compounds. We will analyze metabolism of these drugs by determination of the corresponding CYP enzyme activity, measurement of protein and mRNA levels and determination of zonal expression in tissue samples obtained from different liver lobes to account for heterogeneity. Liver regeneration will be assessed immediately after surgery and within the first postoperative week by addressing liver-to-body-weight ratios, volume and functional recovery as well as proliferation of hepatocytes.These results will be compared to detailed MRI assessment of liver volume, perfusion and function. Our results will be complementary to investigations of the carbohydrate/lipid metabolism and a detailed gene expression analysis. Thus, a comprehensive network of metabolic control assessment as a function of liver perfusion will be generated.All experimental data together with corresponding clinical data will serve as input for the integrated computational models needed for spatially resolved prediction of regeneration and functional recovery of the future liver remnant after liver surgery. As a result, prediction of function and risk stratification for patients undergoing (e)PHX will be improved.

接受扩大肝切除((E)PHX)的患者术后发生肝功能障碍甚至肝功能衰竭的风险很高，尤其是在既有肝病的情况下。我们的研究小组QuaLiPerF旨在利用系统医学方法加强对健康、脂肪变性和手术后再生肝脏的肝脏灌注和功能之间的数量和空间关系的理解。本项目将重点评估灌注扰动和灌注损伤对肝功能丧失和恢复的影响。我们假设，血流灌注的空间不均一性与肝细胞的功能表现和再生过程中的增殖相匹配。我们的目的是通过a)在小叶和小叶尺度上对肝脏灌注量和脂肪变性进行空间分辨量化，b)探索与肝细胞增殖相关的测试性化合物代谢的容量和空间分布，来评估肝脏灌注对正常肝脏、脂肪变性和再生肝脏中试验化合物代谢的影响。为了达到这一目标，我们将使用三种不同的灌流扰动方法在大鼠模型中研究肝脏灌注损伤：肝脏脂肪变性、门静脉结扎和肝切除。动物将接受详细的肝脏血流动力学和微循环评估，使用侧流暗场成像和揭示组织氧合的光学传感器。探测多个肝叶将揭示肝脏血流灌注的异质性。测试化合物代谢用于肝功能的跨尺度评估。我们将在应用五种不同的测试化合物后进行药代动力学研究。我们将通过测定相应的CYP酶活性、测定蛋白质和信使核糖核酸水平以及从不同肝叶获取的组织样本中的区带表达来分析这些药物的代谢，以解释异质性。术后即刻和术后第一周内将通过测量肝脏与体重的比率、体积和功能恢复以及肝细胞的增殖来评估肝脏再生。这些结果将与肝脏体积、灌注量和功能的详细MRI评估相比较。我们的结果将是对碳水化合物/脂肪代谢的研究和详细的基因表达分析的补充。所有的实验数据和相应的临床数据将作为综合计算模型的输入，用于对未来肝脏手术后残留肝脏的再生和功能恢复进行空间分辨预测。因此，对接受(E)PHX的患者的功能和风险分层的预测将得到改善。