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包括控制出血和扩容。根据出血的严重程度和损伤与止血之间的时间差，一些出血性休克患者尽管复苏，仍可能进入不可逆的循环衰竭。 我们现在知道，循环休克，通过流变学和缺血过程，诱导血液动力学，代谢和超急性炎症反应，以复杂的方式相互作用，并可能导致难治性低血压和不可逆性休克的发展。我们已经证明，“实时”监测骨骼肌和其他器官中的pH值、氧合和二氧化碳测定与出血性损伤的严重程度相关。然而，这些测量结果并没有直接与炎症过程相关，急性炎症对不可逆性休克的作用也没有得到很好的理解。同时，我们已经开发和校准了一个数学模型，描述了急性炎症介质在失血性休克。虽然通知循环介质，该模型表示的生理紊乱经历的个别器官的全球，目前理论上，组织功能障碍方程。我们假设，与循环衰竭相关的组织功能障碍的程度是全球能量衰竭和随后的急性炎症的反映，我们可以测量和数学建模。不可逆性休克可能是由于短时间的严重失血，或更轻微的持续出血，和/或延迟或不充分的复苏。我们建议在小鼠和猪中进行一系列系统的实验来描述不可逆性休克。这些实验将被集成在以前开发的数学框架。我们提出了以下两个具体目标：1）表征小鼠的循环衰竭，并增加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）验证组织灌注不足的几种标志物告知猪休克后炎症数学模型的能力，并提供具体的结果预测。在这些特定目标的范围内，我们将测试林格氏丙酮酸乙酯溶液（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性休克的结局。这些治疗失血性休克的新方法可以通过识别高风险、高死亡率的受害者以及帮助评估多人伤亡情况下细胞功能的严重性或不可逆转性来挽救战场上的生命。在更基本的层面上，这项研究将推动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.