Metabolic-Inflammatory Systems in Irreversible Shock

描述(由申请人提供)： 目前对严重出血性创伤患者的治疗主要包括控制出血和扩容。根据出血的严重程度和损伤和止血之间的时间间隔，一些失血性休克患者可能会进入不可逆转的循环衰竭，尽管复苏了。我们现在了解到，循环休克通过流变学和缺血过程，诱导血流动力学、代谢和超急性炎症反应，这些反应以复杂的方式相互作用，可能导致顽固性低血压和不可逆休克的发展。我们已经证明，“实时”监测骨骼肌和其他器官的pH值、氧合和二氧化碳分压与出血性损伤的严重程度相关。然而，这些测量并没有与炎症过程直接相关，也没有很好地了解急性炎症对不可逆性休克的贡献。同时，我们开发并校准了一个描述失血性休克中急性炎症介质的数学模型。尽管受到循环介质的影响，但该模型通过一个目前理论上的整体组织功能障碍方程表达了单个器官所经历的生理紊乱。我们假设，与循环衰竭相关的组织功能障碍的程度反映了全球能量衰竭和随之而来的急性炎症，我们可以对此进行测量和数学建模。不可逆的休克可能是由于短暂的严重失血，或更温和的持续出血，和/或延迟或不充分的复苏所致。我们建议在小鼠和猪身上进行一系列系统的实验，以描绘不可逆转的休克。这些实验将被整合到先前开发的数学框架中。我们提出了以下两个具体目标：1)表征小鼠的循环衰竭，并扩大休克后炎症的数学模型，以包括相关的神经内分泌、心血管和组织代谢元素；2)验证几种组织低灌流标志物提供猪休克后炎症的数学模型的能力，并提供特定的结果预测。在这些特定目标的范围内，我们将测试林格丙酮酸乙酯溶液(REPS)的治疗效果，假设在中度失血性休克中已证实的抗炎特性将改善不可逆转休克的预后。这些治疗失血性休克的新方法可以通过识别高风险、高死亡率的受害者，并在多人伤亡的情况下帮助评估细胞功能的严重性或不可逆性，在战场上拯救生命。在更基本的层面上，这项研究将推进复杂系统在生物学中的应用。我们的数学建模方法与相关动物模型中的数据相结合，以及相关的数据分析、拟合和统计问题，将为系统生物学研究定义新的方法。

DESCRIPTION (provided by applicant): Current therapy for severe hemorrhagic trauma patients consists of hemorrhage control and volume expansion. Depending on the severity of the hemorrhage and the time lag between injury and hemostasis, some patients with hemorrhagic shock may enter into irreversible circulatory collapse, despite resuscitation. We now understand that circulatory shock, through rheological and ischemic processes, induces hemodynamic, metabolic, and hyper-acute inflammatory responses that interact in a complex fashion and may lead to the development of refractory hypotension and irreversible shock. We have demonstrated that "real-time" monitoring of pH, oxygenation, and capnometry in skeletal muscle and other organs correlates with the severity of the hemorrhagic insult. However, these measurements have not been correlated directly with the inflammatory process, nor is the contribution of acute inflammation to irreversible shock well understood. In parallel, we have developed and calibrated a mathematical model that describes the mediators of acute inflammation in hemorrhagic shock. Though informed by circulating mediators, this model expresses the physiological derangement experienced by individual organs in terms of a global, currently theoretical, tissue dysfunction equation. We hypothesize that the magnitude of tissue dysfunction associated with circulatory collapse is a reflection of a global energetic failure and ensuing acute inflammation, which we can measure and model mathematically. Irreversible shock may result from severe exsanguination of short duration, or a more subdued, continuous hemorrhage, and/or delayed or inadequate resuscitation. We propose a systematic series of experiments in mice and swine to delineate irreversible shock. These experiments will be integrated within the mathematical framework previously developed. We propose the following two Specific Aims: 1) to characterize circulatory collapse in mice, and to augment a mathematical model of post-shock inflammation to include relevant neuroendocrine, cardiovascular and tissue metabolic elements; and 2) to validate the ability of several markers of tissue hypoperfusion to inform a mathematical model of post-shock inflammation in swine, and to provide specific outcome predictions. Within the scope of these Specific Aims, we will test the therapeutic efficacy of Ringer's Ethyl Pyruvate Solution (REPS), hypothesizing that the proven anti-inflammatory properties in moderate hemorrhagic shock will improve outcome in irreversible shock. These novel approaches to hemorrhagic shock may save lives on the battlefield by identifying high risk, high mortality victims and by aiding in assessing the severity or irreversibility of cell function in a multiple casualty scenario. On a more basic level, this research will advance the use of complex systems in biology. Our approach of mathematical modeling integrated with data in relevant animal models, and the associated data analysis, fitting, and statistics problems, will define new methodologies for systems biology research.