利用肝机灌注纳什平衡模型进行代谢扰动研究:模拟氧化应激和谷胱甘肽补充剂的影响

Angelo Lucia, Korkut Uygun
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摘要

目前的临床标准是静态冷藏(SCS),即在缺氧状态下置于冰上(约 +4°C)保存,这就将肝脏和心脏等代谢活跃组织的保存时间限制在几小时之内。这一时期的缺氧会产生超氧化物和其他来自嘌呤代谢的自由基,这是缺血/再灌注损伤(IRI)的一个公认组成部分。机器灌注是器官保存的最前沿技术,它提供了一种功能性氧合保存方式,可以避免/减轻 IRI。在临床应用中,灌注通常是在一段时间的 SCS 之后进行。缺氧后氧气的出现会导致超氧化物和过氧化氢的产生,但机器灌注还可以控制温度曲线和提供抗氧化剂治疗,从而最大限度地减少此类问题。然而,代谢组学数据很难收集,目前也没有数学模型来合理设计实验或指导临床实践。本文研究了逐渐升温的温度策略和补充谷胱甘肽对减少氧化应激的影响。采用纳什均衡和蒙特卡洛优化相结合的方法,确定了肝脏代谢模型中期热机灌注的最佳渐进升温温度策略。利用这种最佳渐进升温温度策略,采用不同的蒙特卡洛优化方法计算了将过氧化氢浓度维持在正常区域的最低 GSH 要求。此外,还确定了关键代谢物和辅助因子的动态行为。结果表明,随着过氧化氢浓度的增加,最低 GSH 需求量增加,GSH/GSSG 比率降低。此外,在高浓度的过氧化氢条件下,细胞色素 C 会发生功能障碍,导致电子传递链的有用耗氧量和 ATP 合成减少,肝细胞的能量负荷总体下降。
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Metabolic perturbation studies using a Nash Equilibrium model of liver machine perfusion: modeling oxidative stress and effect of glutathione supplementation
The current clinical standard of Static Cold Storage (SCS) which involves preservation on ice (about +4°C) in a hypoxic state limits storage to a few hours for metabolically active tissues such as the liver and the heart. This period of hypoxia during can generate superoxide and other free radicals from purine metabolism, a well-established component of ischemia/reperfusion injury (IRI). Machine perfusion is at the cutting edge of organ preservation, which provides a functional, oxygenated preservation modality that can avoid/attenuate IRI. In clinical application, perfusion usually follows a period of SCS. This presentation of oxygen following hypoxia can lead to superoxide and hydrogen peroxide generation, but machine perfusion also allows manipulation of the temperature profiles and supply of antioxidant treatments, which could be used to minimize such issues. However, metabolomic data is difficult to gather, and there are currently no mathematical models present to allow rational design of experiments or guide clinical practice. In this article, the effects of a gradual warming temperature policy and glutathione supplementation to minimize oxidative stress are studied. An optimal gradual warming temperature policy for mid-thermic machine perfusion of a liver metabolic model is determined using a combination of Nash Equilibrium and Monte Carlo optimization. Using this optimal gradual warming temperature policy, minimum GSH requirements to maintain hydrogen peroxide concentrations in the normal region are calculated using a different Monte Carlo optimization methodology. In addition, the dynamic behavior of key metabolites and cofactors are determined. Results show that the minimum GSH requirement increases and that the ratio of GSH/GSSG decreases with increasing hydrogen peroxide concentration. In addition, at high concentrations of hydrogen peroxide it is shown that cytochrome C undergoes dysfunction leading to a decrease in useful oxygen consumption and ATP synthesis from the electron transport chain and an overall reduction in the energy charge for the liver cells.
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