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: 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
• 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

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)： 本研究旨在探讨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循环在以下过程中起着不可或缺的作用 严重脓毒症的病理生理学，是一种发病率和死亡率高的疾病，其特征是全身炎症和氧化应激失控，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。一氧化氮合酶以其天然的偶联形式，利用精氨酸作为底物来生产一氧化氮和瓜氨酸。去偶联时，NOS优先产生超氧自由基(O2-)，与NO反应生成过氧亚硝酸根和其他活性氧物种(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相互作用，特别是在肺内，导致膜流动性和功能改变以及ALI的临床表现。在脓毒症中，一氧化氮合酶还会增加一氧化氮的产生，导致全身血管扩张和炎症恶化，这与氧化应激增加一起导致器官功能障碍的发展，尤其是ALI。人体需要有规律的一氧化氮合酶活性来维持体内平衡。瓜氨酸既是精氨酸的底物，又是一氧化氮合酶的反馈抑制剂，可以重建尿素/一氧化氮循环稳态，减轻炎症和氧化应激，预防或减轻严重脓毒症的ALI。我们假设，通过增加血浆瓜氨酸和精氨酸水平，给予瓜氨酸可以安全地恢复一氧化氮合酶的动态平衡。这种恢复的动态平衡将导致一氧化氮和氧化应激的减少，从而防止ALI和其他器官衰竭的发展和/或进展，并改善严重脓毒症患者的临床结局。本应用的具体目的是证明，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的产生；2)安全且不会加剧血管运动不稳定和/或低血压；以及3)改善临床结果，包括预防ALI的发生和发展。范德比尔特大学医学中心将通过其几个ICU提供环境，进行一项随机、安慰剂对照的临床试验，调查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，包括血浆氨基酸、一氧化氮代谢产物和炎性细胞因子的水平。尿液和呼吸冷凝液中的异前列腺素、异呋喃和硝基酪氨酸将被检测为氧化应激的标志。安全性将受到密切监测，特别是通过血管加压药依赖指数和净液体平衡来衡量血管运动稳定性。比较P/F、S/F比值和肺损伤评分，评价ALI的程度。临床结果的差异，包括器官功能障碍、呼吸机时间和存活率也将被评估。

项目成果

The ongoing challenge of evaluating rescue therapies in acute respiratory distress syndrome*.

评估急性呼吸窘迫综合征的救援疗法所面临的持续挑战*。

• DOI: 10.1097/ccm.0000000000000390
• 发表时间: 2014
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Keriwala,RajD;Rice,ToddW
• 通讯作者: Rice,ToddW

A history of smoking is associated with improved survival in patients treated with mild therapeutic hypothermia following cardiac arrest.

• DOI: 10.1016/j.resuscitation.2013.08.275
• 发表时间: 2014-01
• 期刊: Resuscitation
• 影响因子: 6.5
• 作者: Pollock JS;Hollenbeck RD;Wang L;Janz DR;Rice TW;McPherson JA
• 通讯作者: McPherson JA