Optimal Amino Acid Nutrition in Sepsis

描述(申请人提供)：败血症会引起体内多个系统的代谢压力。尽管在脓毒症中用适当的营养支持器官和组织代谢的重要性是公认的，但目前的营养方法在预防肌肉损失和肠道萎缩方面普遍不成功。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特定氨基酸配方的反应。我们最重要的假设是，有一种主要基于必需氨基酸(EaAs)的独特配方，将最大限度地刺激肌肉和肠道粘膜的蛋白质合成，同时保持肝脏的蛋白质合成。为了解决我们的一般假设，我们将解决以下特定目标：特定目标1：测试猪的脓毒症导致肌肉和肠道粘膜蛋白净分解的假设；肠道精氨酸产生的减少；以及肝脏急性时相蛋白(以纤维蛋白原为代表)和白蛋白合成的刺激。具体目标2：检验与特定氨基酸配方的反应有关的一系列假说。这些配方是：在猪蛋白中发现的EaS和非EaS的平衡混合物；仅EaaS的混合物；以及EaaS加12.5%瓜氨酸的混合物。具体目标3：验证一种假设，即与代表猪肌肉的完全平衡的EaAs和非EaaS混合物相比，摄入EaaS的氨基酸混合物(无论是否含有瓜氨酸)将使血液酸度和尿素产生的变化降至最低。具体的目标将在用留置导管准备的慢性仪器化猪模型中进行测试，以便能够在肠道、肝脏和肌肉中进行采样。动静脉采样和稳定同位素方法的结合将使所有终点的量化成为可能。这项研究的结果应该为新的营养配方提供基础，以专门支持脓毒症的器官和组织代谢。公共卫生相关性：这项研究的结果应该为一种新的营养配方提供基础，以专门支持脓毒症患者的器官和组织代谢。

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.