Optimal Amino Acid Nutrition in Sepsis

描述（由申请人提供）：脓毒症诱导体内多个系统的代谢应激。尽管在脓毒症中通过适当的营养支持器官和组织代谢的重要性已得到公认，但目前的营养方法在预防肌肉损失和肠道萎缩方面通常不成功。我们建议量化肌肉、肠道和肝脏中蛋白质合成对旨在刺激蛋白质合成的氨基酸特定制剂的响应。我们最重要的假设是，有一种主要基于必需氨基酸（EAA）的独特制剂，它将最大限度地刺激肌肉和肠粘膜中的蛋白质合成，同时维持肝脏中的蛋白质合成。为了解决我们的一般假设，我们将解决以下具体目标：具体目标1：检验猪败血症诱导肌肉和肠粘膜蛋白净分解的假设;肠中精氨酸产量减少;以及刺激肝脏急性期蛋白（以纤维蛋白原为代表）和白蛋白合成。具体目标2：检验与特定氨基酸制剂反应相关的一系列假设。这些配方是：在猪蛋白质中发现的EAA和非EAA的平衡混合物;仅EAA的混合物;以及EAA加12.5%瓜氨酸的混合物。具体目标3：检验以下假设：与代表猪肌肉的EAA和非EAA完全平衡混合物的相应量相比，摄入基于EAA的氨基酸混合物（含或不含瓜氨酸）将最大限度地减少血液酸度和尿素生成的变化。具体目标将在使用留置导管制备的长期仪器化猪模型中进行测试，以便能够通过肠道、肝脏和肌肉进行采样。动静脉采样和稳定同位素方法的组合将能够量化所有终点。这项研究的结果应该提供一个新的营养配方，专门支持器官和组织代谢败血症的基础。公共卫生相关性：这项研究的结果应该提供一个新的营养配方，专门支持器官和组织代谢败血症的基础。

DESCRIPTION (provided by applicant): Sepsis induces a metabolic stress on multiple systems in the body. Despite the well-recognized importance of supporting organ and tissue metabolism in sepsis with appropriate nutrition, current nutritional approaches are generally unsuccessful at preventing muscle loss and gut atrophy. We propose to quantify the response of protein synthesis in the muscle, gut, and liver to specific formulations of amino acids designed to stimulate protein synthesis. Our overriding hypothesis is that there is a unique formulation based primarily on essential amino acids (EAAs) that will maximally stimulate protein synthesis in muscle and gut mucosa, while maintaining protein synthesis in the liver. In order to address our general hypothesis we will address the following specific aims: Specific Aim 1: To test the hypothesis that sepsis in pigs induces a net breakdown of muscle and gut mucosal protein; a reduced production of arginine in the gut; and a stimulation of liver acute phase proteins (represented by fibrinogen) and albumin synthesis. Specific Aim 2: To test a series of hypotheses related to the responses to specific formulations of amino acids. Those formulations are: a balanced mixture of EAAs and non-EAAs in the profile found in pig protein; a mixture of only EAAs; and, a mixture of EAAs plus 12.5% citrulline. Specific Aim 3: To test the hypothesis that ingestion of mixtures of amino acids based on EAAs (either with or without citrulline) will minimize changes in blood acidity and urea production as compared to the corresponding amount of the complete balanced mixture of EAAs and non-EAAs representing pig muscle. The specific aims will be tested in a chronically instrumented pig model prepared with indwelling catheters to enable sampling across the gut, liver, and muscle. The combination of arteriovenous sampling and stable isotope methodology will enable quantification of all endpoints. The results of this study should provide the basis for a new nutritional formulation to specifically support organ and tissue metabolism in sepsis. PUBLIC HEALTH RELEVANCE: The results of this study should provide the basis for a new nutritional formulation to specifically support organ and tissue metabolism in sepsis.