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Therapeutic and Metabolic Responses of Citrulline vs. Arginine Supplementation

瓜氨酸与精氨酸补充剂的治疗和代谢反应

基本信息

批准号：
10654598
负责人：
DOUGLAS G BURRIN
金额：
$ 29.03万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10654598
关键词：
Acute-Phase Proteins Address Affect Amino Acids Ammonia Arginine Arginine deiminase Blood Pressure Blood Vessels Cardiovascular Physiology Cell physiology Childhood Citrulline Critical Illness Development Effectiveness Endotoxemia Endotoxic Shock Endotoxins Enzymes Event Failure Family suidae Functional disorder Half-Life Hepatic Hypotension Hypotensives Hypoxia Immunity Inflammation Inflammatory Intervention Liver Mental Depression Metabolic Metabolism Microcirculation Modeling Molecular Mus NOS2A gene Nitric Oxide Operative Surgical Procedures Organ Organ failure Outcome Pathway interactions Patients Perfusion Plasma Play Process Production Protein Biosynthesis Protein Isoforms Protocols documentation Recommendation Recycling Regulation Research Role Sepsis Septic Shock Severities Signaling Molecule Site Supplementation Testing Therapeutic Time Tissues Tracer Work arginase blood pressure control cardiovascular effects cell type immunogenicity improved methicillin resistant Staphylococcus aureus mortality organ injury oxidative damage pathogenic Escherichia coli porcine model preservation prevent protein biomarkers response septic septic patients stable isotope tissue injury

项目摘要

Arginine depletion is a phenomenon observed in septic patients, and is associated with greater mortality as its severity increases. Among numerous other functions, arginine is the precursor for the signaling molecule nitric oxide that plays a central role in immunity, in the control of blood pressure, and in the regulation of the microcirculation and tissue perfusion. Although the mechanism responsible for the depletion and fate of arginine has yet to be identified, arginine supplementation has been proposed to restore arginine availability. However, it is not clear if arginine supplementation is always effective or beneficial, because it can result in hyperproduction of nitric oxide and contribute to hypotension, cardio depression and vascular hyporeactivity in septic shock. Supplementing with citrulline, the precursor for the endogenous synthesis of arginine, has the potential to be more effective than arginine supplementation, but may also result in excessive nitric oxide production. An alternative approach that simultaneously addresses the depletion of arginine and hyperproduction of nitric oxide is the use of ADI-PEG 20. This pegylated bacterial enzyme catalyzes the conversion of arginine into citrulline, which can be re-utilized by the citrulline `recycling pathway'. This pathway provides intracellular arginine to sustain most processes that require this amino acid, but at the same time modulating the hyperproduction of nitric oxide during sepsis. Our central hypothesis is that sepsis causes dysregulation of arginine metabolism resulting in plasma arginine depletion and contributing to macro- and microcirculatory failure that leads to organ dysfunction. The objectives of the proposed research are to elucidate the mechanisms of ARG depletion in pediatric swine models of sepsis and evaluate different strategies to restore ARG availability, prevent hypotension and mitigate tissue injury. To test our central hypothesis and attain our objectives we propose the following specific aims: Specific Aim1: Quantify the disposal rate of arginine by the liver and the pathways involved in its utilization in swine models of sepsis. Specific Aim2: Determine arginine availability in septic pigs supplemented with citrulline or arginine and its effect on nitric oxide production, blood pressure, protein synthesis and markers of tissue injury. Specific Aim3: Determine arginine availability and cardiovascular function, including blood pressure and tissue markers of hypoxia during sepsis in ADI-PEG 20-arginine-depleted pigs. To achieve these aims we will use methicillin- resistant S. aureus and pathogenic E. Coli swine models of sepsis-induced multiple organ dysfunction. A multitracer stable isotope protocol will be used to quantify whole body and hepatic arginine metabolism, and the analysis of the relevant enzymes and transporters will provide the molecular basis for the changes observed. Blood pressure, plasma metabolites, and markers of organ function and tissue injury will be analyzed to determine the effect of the different interventions on cardiovascular function, tissue perfusion and organ injury.

精氨酸耗竭是在脓毒症患者中观察到的一种现象，随着其严重程度的增加，与更高的死亡率相关。在众多其他功能中，精氨酸是信号分子一氧化氮的前体，在免疫、血压控制、微循环和组织灌注调节中起着核心作用。尽管造成精氨酸消耗和命运的机制尚未确定，但已提出补充精氨酸以恢复精氨酸的可用性。然而，目前尚不清楚补充精氨酸是否总是有效或有益的，因为它可以导致一氧化氮的过量产生，并有助于感染性休克的低血压、心脏抑制和血管反应性降低。补充瓜氨酸（内源性精氨酸合成的前体）可能比补充精氨酸更有效，但也可能导致过量的一氧化氮产生。另一种同时解决精氨酸耗竭和一氧化氮过量问题的方法是使用ADI-PEG 20。这种聚乙二醇化的细菌酶催化精氨酸转化为瓜氨酸，瓜氨酸可以通过瓜氨酸“循环途径”重新利用。该途径提供细胞内精氨酸来维持大多数需要这种氨基酸的过程，但同时调节败血症期间一氧化氮的过量产生。我们的中心假设是败血症导致精氨酸代谢失调，导致血浆精氨酸消耗，并导致大循环和微循环衰竭，导致器官功能障碍。本研究的目的是阐明小儿猪脓毒症模型中ARG耗竭的机制，并评估恢复ARG可用性、预防低血压和减轻组织损伤的不同策略。为了验证我们的中心假设并实现我们的目标，我们提出了以下具体目标：具体目标1：量化肝脏对精氨酸的处理率及其在猪败血症模型中使用的途径。特定目的2：确定在败血症猪中补充瓜氨酸或精氨酸的精氨酸利用率及其对一氧化氮生成、血压、蛋白质合成和组织损伤标志物的影响。特定目的3：测定ADI-PEG 20-精氨酸耗竭猪败血症期间的精氨酸可用性和心血管功能，包括血压和组织缺氧标志物。为了达到这些目的，我们将使用耐甲氧西林金黄色葡萄球菌和致病性大肠杆菌猪模型来研究败血症诱导的多器官功能障碍。多示踪稳定同位素方案将用于量化全身和肝脏精氨酸代谢，相关酶和转运体的分析将为观察到的变化提供分子基础。将分析血压、血浆代谢物、器官功能和组织损伤标志物，以确定不同干预措施对心血管功能、组织灌注和器官损伤的影响。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Arginine depletion by arginine deiminase does not affect whole protein metabolism or muscle fractional protein synthesis rate in mice.

DOI：
10.1371/journal.pone.0119801
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Marini JC;Didelija IC
通讯作者：
Didelija IC

Protein requirements: are we ready for new recommendations?

蛋白质需求：我们准备好接受新的建议了吗？

DOI：
10.3945/jn.114.203935
发表时间：
2015
期刊：
The Journal of nutrition
影响因子：
0
作者：
Marini,JuanC
通讯作者：
Marini,JuanC

Citrulline Generation Test: What Does It Measure?

瓜氨酸生成测试：它测量什么？

DOI：
10.1002/jpen.1462
发表时间：
2019
期刊：
JPEN. Journal of parenteral and enteral nutrition
影响因子：
0
作者：
Mohammad,MahmoudA;Didelija,InkaC;Stoll,Barbara;Marini,JuanC
通讯作者：
Marini,JuanC

The Citrulline Recycling Pathway Sustains Cardiovascular Function in Arginine-Depleted Healthy Mice, but Cannot Sustain Nitric Oxide Production during Endotoxin Challenge.

瓜氨酸回收途径维持精氨酸耗尽的健康小鼠的心血管功能，但在内毒素挑战期间不能维持一氧化氮的产生。

DOI：
10.1093/jn/nxy065
发表时间：
2018
期刊：
The Journal of nutrition
影响因子：
0
作者：
Yuan,Yang;Mohammad,MahmoudA;Betancourt,Ancizar;Didelija,InkaC;Yallampalli,Chandrasekar;Marini,JuanC
通讯作者：
Marini,JuanC

Dietary arginine requirements for growth are dependent on the rate of citrulline production in mice.

生长所需的膳食精氨酸取决于小鼠瓜氨酸的产生率。