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: 8424973
• 负责人: TODD W RICE
• 金额: $ 18.56万
• 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/8424973
• 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.

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）方面的作用。尿素/NO循环在以下方面起着不可或缺的作用： 严重脓毒症病理生理学，一种具有高发病率和死亡率的疾病，其特征在于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，从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产生NO和瓜氨酸。当解偶联时，NOS优先产生超氧自由基（O2-），其与NO反应形成过氧亚硝酸根和其他活性氧物质（ROS）。这些ROS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（尤其是肺中的内皮细胞）相互作用，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还增加NO的产生，导致全身血管舒张和炎症恶化，这沿着增加的氧化应激有助于器官功能障碍的发展，特别是ALI。身体需要调节NOS活性以维持体内平衡。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，减轻炎症和氧化应激，预防或减轻严重脓毒症中的ALI。我们假设，瓜氨酸给药可通过增加血浆瓜氨酸和精氨酸水平，安全地恢复NOS的稳态。这种恢复的体内平衡将导致一氧化氮和氧化应激的产生减少，从而预防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局。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，减少患者的氧化应激和NO生成; 2）安全，不会加剧血管不稳定和/或低血压; 3）改善临床结局，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几个ICU为开展一项随机、安慰剂对照临床试验提供环境，研究静脉注射瓜氨酸对严重脓毒症患者的影响。实验室资源可用于调查生化反应的变化，包括氨基酸，一氧化氮代谢产物和炎症细胞因子的血浆水平。将测量尿液和呼吸冷凝液中的异前列烷、异呋喃和硝基酪氨酸，作为氧化应激的标志物。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稳定性。将比较P/F和S/F比值以及肺损伤评分，以评估ALI的程度。还将评估临床结局的差异，包括器官功能障碍、呼吸机时间和生存率。