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

• 批准号: 8240853
• 负责人: TODD W RICE
• 金额: $ 19.5万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240853
• 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

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. PUBLIC HEALTH RELEVANCE: Currently treatments for severe sepsis resulting in acute lung injury are limited with none that prevent the development of acute lung injury. Urea cycle dysfunction is a key part of the inflammatory and oxidative stress cascades leading to acute lung injury in severely septic patients. Administration of the amino acid citrulline can re-establish autoregulation of nitric oxie synthase and homeostasis of the urea cycle, reduce inflammation and oxidative stress, and prevent or mitigate organ dysfunction, especially injury to the lungs, in these patients. (End of Abstract)

描述（由申请人提供）： 该应用的目的是研究瓜氨酸在预防或米蒂加蛋白急性肺损伤（ALI）中的作用。尿素/无周期在 严重的脓毒症病理生理学，一种具有高发病率和死亡率的疾病，其特征是不受控制的全身性炎症和氧化应激导致器官功能障碍。炎症会导致血浆瓜氨酸缺乏，从而导致精氨酸缺乏和一氧化氮合酶（NOS）的解偶联。 NOS以天然耦合形式使用精氨酸作为产生NO和瓜氨酸的底物。当取消耦合时，NOS优先会产生超氧化物自由基（O2-），该自由基与无反应形成过氧亚硝酸盐和其他活性氧（ROS）。这些ROS刺激单核细胞产生并释放额外的促炎细胞因子，从而进一步传播和延长炎症性级联反应。这些自由基还通过脂质过氧化与内皮细胞相互作用，尤其是在肺中，从而导致膜的流动性和功能改变以及ALI的临床图片。在败血症中，NOS还增加了无导致全身性血管舒张和恶化的炎症的产生，氧化应激的增加会导致器官功能障碍的发展，尤其是ALI。人体需要调节的NOS活动以维持稳态。瓜氨酸通过作为NOS的精氨酸和反馈抑制剂的底物可以重新建立尿素/无周期稳态，减少炎症和氧化应激，并预防或减轻严重败血症的ALI。我们假设瓜氨酸的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育和/或进展，并改善严重败血症患者的临床结果。本应用的具体目的是证明，静脉注射瓜氨酸对严重的化粪池患者的施用会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NO的氧化应激； 2）安全，不要加剧血管舒适的不稳定性和/或低血压； 3）改善临床结果，包括预防ALI的发展和发展。 范德比尔特大学医学中心通过其几个ICU将提供环境，以进行随机的，安慰剂对照的临床试验，研究IV citrulline N患者患有严重败血症的患者的作用。实验室资源可用于研究生化反应的变化，包括氨基酸的血浆水平，一氧化氮代谢物和炎性细胞因子。尿液和呼吸冷凝物的异丙烷，异呋喃和硝基酪氨酸将作为氧化应激的标记。安全性将受到密切监测，特别是血管舒张器依赖性指数和净流体平衡所测量的血管舒缩稳定性。比较P/F和S/F比和肺损伤评分，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，呼吸机时间和存活率。 公共卫生相关性： 目前，导致急性肺损伤导致严重败血症的治疗受到限制，没有阻止急性肺损伤的发展。尿素周期功能障碍是炎症和氧化应激级联反应的关键部分，导致严重化粪池患者急性肺损伤。在这些患者中，氨基酸瓜氨酸的给药可以重新建立对尿素周期的一氧氧蛋白酶和尿素周期稳态的自动调节，并预防或减轻或减轻这些患者的器官功能障碍，尤其是对肺部的损伤。 （抽象的结尾）