Citrulline to Prevent or Mitigate Acute Lung Injury in Severe Sepsis

瓜氨酸预防或减轻严重脓毒症的急性肺损伤

基本信息

批准号：
8610942
负责人：
TODD W RICE
金额：
$ 30.58万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610942
关键词：
3-nitrotyrosine Academic Medical Centers Accounting Activity Cycles Acute Lung Injury Adult Adverse effects Adverse event Amino Acids Arginine Biochemical Blinded Blood Pressure Bone Marrow Transplantation Cardiac Surgery procedures Cells Child Citrulline Clinical Clinical Trials Controlled Clinical Trials Coupled Coupling Dependency Development Disease Dose Endothelial Cells Enteral Environment Enzyme Inhibition Enzymes Etiology Exhalation Feedback Fluid Balance Free Radicals Functional disorder Gastrointestinal tract structure Homeostasis Hospital Mortality Hour Hypotension Inflammation Inflammatory Infusion procedures Injury Intravenous Isoprostanes Kidney Laboratories Length of Stay Lipid Peroxidation Liver Liver Mitochondria Lung Measures Membrane Fluidity Metabolism Monitor Morbidity - disease rate NG-Nitroarginine Methyl Ester Nitric Oxide Nitric Oxide Synthase Organ Organ failure Ornithine Ornithine Carbamoyltransferase Outcome Oxidants Oxidative Stress Patients Peroxonitrite Placebo Control Plasma Play Pneumonia Prevention Production Randomized Reactive Oxygen Species Reporting Resources Role Safety Sepsis Septic Shock Signal Transduction Superoxides Syndrome System Testing Time Tissues Transplant Recipients Urea Urine Vasoconstrictor Agents Vasodilation Vasomotor Ventilator abstracting arginase cytokine dosage human NOS2A protein immune function improved indexing inhibitor/antagonist intravenous administration lung injury monocyte mortality patient population placebo controlled study pressure prevent response secondary outcome septic urea cycle urinary

项目摘要

DESCRIPTION (provided by applicant): The purpose of this application is to investigate the role of citrulline in preventing or mitigatin acute lung injury (ALI) in patients with severe sepsis. The urea/NO cycle plays an integral role in severe sepsis pathophysiology, a disease with high morbidity and mortality characterized by uncontrolled systemic inflammation and oxidative stress leading to organ dysfunction. Inflammation results in plasma citrulline deficiency which leads to arginine deficiency and uncoupling of nitric oxide synthase (NOS). NOS, in its natural coupled form, utilizes arginine as substrate for producing NO and citrulline. When uncoupled, NOS preferentially produces superoxide radicals (O2-) which react with NO to form peroxynitrite and other reactive oxygen species (ROS). These ROS stimulate monocytes to produce and release additional pro-inflammatory cytokines, further propagating and prolonging the inflammatory cascade. These free radicals also interact with endothelial cells, especially in the lung, via lipid peroxidation causing altered membrane fluidity and function and the clinical picture of ALI. In sepsis, NOS also increases production of NO resulting in systemic vasodilation and worsening inflammation, which along with the increased oxidative stress contributes to the development of organ dysfunction, especially ALI. The body needs regulated NOS activity to maintain homeostasis. Citrulline, by serving as both substrate for arginine and feedback inhibitor of NOS, can re-establish urea/NO cycle homeostasis, reduce inflammation and oxidative stress and prevent or mitigate ALI in severe sepsis. We hypothesize that citrulline administration will safely restore homeostasis of NOS by increasing both plasma citrulline and arginine levels. This restored homeostasis will result in reduced production of nitric oxide and oxidative stress, thereby preventing development and/or progression of ALI and other organ failures and improving clinical outcomes in patients with severe sepsis. The specific aims of this application are to demonstrate that administration of IV citrulline to severely septic patients will 1) increase both plasma citrulline and arginine levels and reduce oxidative stress and production of NO in patients; 2) be safe and not exacerbate vasomotor instability and/or hypotension; and 3) improve clinical outcomes, including prevention of both the development and progression of ALI. Vanderbilt University Medical Center, through its several ICUs, will provide the environment to conduct a randomized, placebo-controlled clinical trial investigating the effects of IV citrulline n patients with severe sepsis. Laboratory resources are available to investigate changes in biochemical responses, including plasma levels of amino acids, nitric oxide metabolites, and inflammatory cytokines. Isoprostanes, isofurans, and nitrotyrosine from urine and breath condensate will be measured as markers of oxidative stress. Safety will be closely monitored, especially vasomotor stability as measured by vasopressor dependency index and net fluid balance. P/F and S/F ratios and lung injury score will be compared to evaluate the extent of ALI. Differences in clinical outcomes, including organ dysfunction, ventilator time, and survival will also be evaluated.

描述（由申请人提供）：本申请的目的是研究瓜氨酸在预防或减轻严重脓毒症患者急性肺损伤 (ALI) 中的作用。尿素/NO 循环在严重脓毒症的病理生理学是一种发病率和死亡率很高的疾病，其特征是不受控制的全身炎症和氧化应激导致器官功能障碍。炎症导致血浆瓜氨酸缺乏，进而导致精氨酸缺乏和一氧化氮合酶（NOS）解偶联。 NOS以其天然偶联形式利用精氨酸作为底物来产生NO和瓜氨酸。当解偶联时，NOS 优先产生超氧自由基 (O2-)，与 NO 反应形成过氧亚硝酸盐和其他活性氧 (ROS)。这些活性氧刺激单核细胞产生和释放额外的促炎细胞因子，进一步传播和延长炎症级联反应。这些自由基还通过脂质过氧化作用与内皮细胞相互作用，尤其是在肺中，导致膜流动性和功能改变以及 ALI 的临床表现。在脓毒症中，NOS 还会增加 NO 的产生，导致全身血管舒张和炎症恶化，再加上氧化应激的增加，导致器官功能障碍，尤其是 ALI。身体需要调节 NOS 活性来维持体内平衡。瓜氨酸作为精氨酸的底物和 NOS 的反馈抑制剂，可以重建尿素/NO 循环稳态，减少炎症和氧化应激，并预防或减轻严重脓毒症中的 ALI。我们假设瓜氨酸给药将通过增加血浆瓜氨酸和精氨酸水平来安全地恢复 NOS 的稳态。这种恢复的稳态将导致一氧化氮和氧化应激的产生减少，从而防止 ALI 和其他器官衰竭的发生和/或进展，并改善严重脓毒症患者的临床结果。本申请的具体目的是证明对严重脓毒症患者静脉注射瓜氨酸将：1）增加血浆瓜氨酸和精氨酸水平，并减少患者的氧化应激和一氧化氮的产生； 2) 安全且不会加剧血管舒缩不稳定和/或低血压； 3) 改善临床结果，包括预防 ALI 的发生和进展。范德比尔特大学医学中心将通过其多个 ICU 提供环境来进行一项随机、安慰剂对照的临床试验，研究静脉注射瓜氨酸对严重脓毒症患者的影响。实验室资源可用于研究生化反应的变化，包括氨基酸、一氧化氮代谢物和炎症细胞因子的血浆水平。尿液和呼吸冷凝物中的异前列腺素、异呋喃和硝基酪氨酸将作为氧化应激的标志物进行测量。将密切监测安全性，特别是通过血管加压药依赖指数和净液体平衡测量的血管舒缩稳定性。将 P/F 和 S/F 比值与肺损伤评分进行比较，以评估 ALI 的程度。还将评估临床结果的差异，包括器官功能障碍、呼吸机时间和生存率。