利用荧光素钠在体外机器灌注肝脏中处置的 PBPK 模型评估肝脏缺血再灌注损伤的程度。

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Christopher E Monti, Seung-Keun Hong, Said H Audi, Whayoung Lee, Amit Joshi, Scott S Terhune, Joohyun Kim, Ranjan K Dash
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引用次数: 0

摘要

缺血再灌注损伤(IRI)是肝移植的固有风险。体外肝脏机器灌注(MP)是一种新兴的器官保存技术,可减轻IRI,尤其是在肝脏受到长时间温缺血(WIT)的情况下。然而,在 MP 期间量化 WIT 生物反应的方法尚未建立。之前的研究利用基于生理学的药代动力学(PBPK)模型证明,示踪剂分子荧光素钠(SF)的肝脏转运和胆汁排泄减少与原位 WIT 的增加相关。此外,这些研究还提出,肝细胞管膜转运体多药耐药性相关蛋白 2(MRP2)的细胞内螯合导致 MRP2 活性(最大转运速度;Vmax)降低是 SF 胆汁排泄减少的潜在机制。我们对现有的 PBPK 模型进行了调整,以考虑体内肝脏 MP 的情况,并对该模型的 6 参数版本进行了拟合,以控制 MP 灌注液和胆汁中 SF 的时程测量。然后,我们确定了一些参数,这些参数的值可能对 WIT 的变化不敏感,并对其进行了固定,从而生成了只有 3 个未知参数的简化模型。最后,我们将简化模型拟合到 WIT 不同的每个生物重复 SF 时间过程中,找出每个参数的平均估计值,并使用单因素方差分析对它们进行比较。结果表明,在 WIT 为 30 分钟时,MRP2 的 Vmax 估计值显著下降。这些研究为今后调查体内MP过程中肝脏活力的实时评估奠定了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Assessing the degree of hepatic ischemia-reperfusion injury using physiologically based pharmacokinetic modeling of sodium fluorescein disposition in ex vivo machine-perfused livers.

Ischemia-reperfusion injury (IRI) is an intrinsic risk associated with liver transplantation. Ex vivo hepatic machine perfusion (MP) is an emerging organ preservation technique that can mitigate IRI, especially in livers subjected to prolonged warm ischemia time (WIT). However, a method to quantify the biological response to WIT during MP has not been established. Previous studies used physiologically based pharmacokinetic (PBPK) modeling to demonstrate that a decrease in hepatic transport and biliary excretion of the tracer molecule sodium fluorescein (SF) could correlate with increasing WIT in situ. Furthermore, these studies proposed intracellular sequestration of the hepatocyte canalicular membrane transporter multidrug resistance-associated protein 2 (MRP2) leading to decreased MRP2 activity (maximal transport velocity; Vmax) as the potential mechanism for decreased biliary SF excretion. We adapted an extant PBPK model to account for ex vivo hepatic MP and fit a six-parameter version of this model to control time-course measurements of SF in MP perfusate and bile. We then identified parameters whose values were likely insensitive to changes in WIT and fixed them to generate a reduced model with only three unknown parameters. Finally, we fit the reduced model to each individual biological replicate SF time course with differing WIT, found the mean estimated value for each parameter, and compared them using a one-way ANOVA. We demonstrated that there was a significant decrease in the estimated value of Vmax for MRP2 at the 30-min WIT. These studies provide the foundation for future studies investigating real-time assessment of liver viability during ex vivo MP.NEW & NOTEWORTHY We developed a computational model of sodium fluorescein (SF) biliary excretion in ex vivo machine perfusion and used this model to assess changes in model parameters associated with the activity of MRP2, a hepatocyte membrane transporter, in response to increasing warm ischemia time. We found a significant decrease in the parameter value describing MRP2 activity, consistent with a role of decreased MRP2 function in ischemia-reperfusion injury leading to decreased secretion of SF into bile.

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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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