Mechanisms of Cell-Free Plasma Hemoglobin-Mediated Renal Injury after Cardiopulmonary Bypass

体外循环后无细胞血浆血红蛋白介导的肾损伤机制

• 批准号: 10054248
• 负责人: Nahmah Kim-Campbell
• 金额: $ 16.02万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054248
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Affect; Age; Antioxidants; Apoptotic; Biochemical; Biological Availability; Biological Markers; Biology; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cell Death; Cells; Child; Childhood; Childhood Injury; Clinical; Clinical Research; Consumption; Creatinine; Critically ill children; Cytoplasm; Data; Disease; Electron Spin Resonance Spectroscopy; Environment; Epithelial Cells; Erythrocytes; Experimental Models; Exposure to; Female; Foundations; Free Radicals; Functional disorder; Future; Gender; Glutathione; Guidelines; Haptoglobins; Heart Diseases; Hemeproteins; Hemoglobin; Hemoglobin concentration result; Hemolysis; Histologic; Histology; Human; Hydrogen Peroxide; Infant; Inflammation; Injury; Injury to Kidney; International; Intervention; Iron; Ischemia; Kidney; Kidney Diseases; Knowledge; LCN2 gene; Lead; Length of Stay; Lipids; Malaria; Measurement; Measures; Mediating; Mentors; Methods; Modeling; Morbidity - disease rate; Nitric Oxide; Nitric Oxide Donors; Nitrites; Operative Surgical Procedures; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Patients; Peroxidases; Pharmaceutical Preparations; Plasma; Porphyrins; Production; Prussian blue; Rattus; Reducing Agents; Renal Blood Flow; Renal function; Reperfusion Therapy; Research; Research Design; Research Personnel; Resources; Risk Factors; Rodent; Rodent Model; Role; Sampling; Scientist; Sepsis; Serum; Sickle Cell Anemia; Stains; Superoxides; Supplementation; Testing; Toxic effect; Tubular formation; Urine; Venous; ascorbate; clinical translation; defined contribution; design; experience; experimental study; haptoglobin-hemoglobin complex; hypoperfusion; improved; in vivo; insight; interest; male; mortality; novel; organ injury; oxidation; oxidative damage; pediatric patients; prospective; renal artery; skills; therapeutic target; translational study

ABSTRACT Cardiopulmonary bypass (CPB) in pediatric cardiac surgery has been refined over the years, yet unfavorable outcomes such as acute kidney injury (AKI), which is associated with mortality and prolonged ICU and hospital length of stay, remains problematic and incompletely understood. Cell-free plasma hemoglobin (PHb) can be produced in large quantities during CPB and other forms of extracorporeal therapy. The ultimate focus of this proposal is to contribute to the knowledge of the pathophysiology and mechanisms of the role of PHb in post-CPB AKI in order to identify clinically meaningful therapies. The research plan for this proposal was designed to examine this in a prospective clinical study while also attempting to have a more mechanistic approach to defining potential therapeutic targets using an in vivo rodent model of extracorporeal therapy. Preliminary data demonstrated the association of PHb with AKI in children undergoing CPB with age and gender-related differences and is associated with decreased nitric oxide (NO) bioavailability and increased indicators of oxidative stress. Recent preliminary data also shows that end products of lipid oxidation (9 and 13-hydroxyoctadecadienoic acid [HODEs]) can be bioactive and lead to increased requirements for vasoactive medications. This proposal focuses on the idea that PHb and PHb-haptoglobin complexes have peroxidase activity that consumes reductants or antioxidants such as ascorbate, glutathione, and nitric oxide (NO) and also leads to the production of HODEs. These biochemical indicators of oxidative stress will be measured in both human and rat samples. The bioactivity of the HODEs, changes in NO bioavailability, and depletion of antioxidants will lead to functional effects (evaluated by need for vasoactive medication, change in renal blood flow, and renal function) and histological evidence of renal injury. The use of a rodent model of extracorporeal therapy will allow invasive measurements of renal blood flow, in vivo NO availability, and ability to evaluate kidney histology. The introduction of targeted interventions in this experimental model, namely nitrite, a NO donor, and MnPP, which eliminates both superoxide and its dismutation product H2O2 (the fuel for peroxidase activity), is thus expected to ameliorate renal injury. This proposal will lead to a greater ability to identify risk factors of PHb-mediated renal injury after CPB and illuminate the mechanisms by which PHb drives AKI. Dr. Kim-Campbell has assembled a mentoring team of internationally recognized investigators led by Dr. Hülya Bayır, an expert in oxidative stress and free radical biology. The available resources, institutional support, and exceptional mentoring environment will provide Dr. Kim-Campbell with the foundation to become an independent clinician scientist with expertise in meaningful mechanistically-supported methods to improve adverse renal outcomes in extracorporeal therapies.

抽象的 多年来，小儿心脏手术中的心肺旁路（CPB）已得到改善，但是 不利的结果，例如急性肾脏损伤（AKI），与死亡率和长期ICU有关 住院时间长度，仍然有问题，并且不完全理解。无细胞血红蛋白 （PHB）可以在CPB和其他形式的体外治疗期间大量生产。最终 该提议的重点是有助于了解病理生理学和机制的知识 CPB后AKI中的PHB以识别临床意义有意义的疗法。该提议的研究计划 旨在在一项前瞻性临床研究中对此进行检查，同时也试图拥有更机械的 使用体内啮齿动物体外治疗模型来定义潜在的治疗靶标的方法。 初步数据证明了PHB与AKI的关联，随着年龄的增长，患有CPB的儿童 与性别相关的差异，与一氧化氮（NO）生物利用度降低并增加有关 氧化应激的指标。最近的初步数据还表明，脂质氧化的最终产物（9和 13-羟基二十二烯酸[HODES]）可能是生物活性的，并导致对血管活性的需求增加 药物。该提案的重点是PHB和PHB Haptoglobin复合物具有过氧化物酶 消耗还原或抗氧化剂的活性，例如抗坏血酸，谷胱甘肽和一氧化氮（NO）和 还导致霍德斯的生产。这些氧化应激的生化指标将在 人类和大鼠样品。霍德斯的生物活性，无生物利用度的变化以及耗尽 抗氧化剂将导致功能效应（通过血管活性药物的需求评估，肾血的变化 流动和肾功能）和肾脏损伤的组织学证据。使用啮齿动物模型的体外模型 治疗将允许对肾血流的侵入性测量，体内无可用性和评估能力 肾脏组织学。在这个实验模型中引入了靶向干预措施，即亚硝酸盐，否 供体和MNPP，它消除了超氧化物及其损失的产品H2O2（过氧化物酶的燃料 活动）因此，预计会改善肾脏损伤。 该建议将导致更大的能力鉴定CPB后PHB介导的肾脏损伤的危险因素 并照亮了PHB驱动AKI的机制。金·坎贝尔博士已经组建了一个心理团队 由氧化应激和自由基专家HülyaBayır博士领导的国际认可的研究人员 生物学。可用的资源，机构支持和卓越的心理环境将为博士提供。 Kim-Cambell的基金会成为一名独立的临床科学家，并具有有意义的专家 机械支撑的方法可以改善体外疗法的不良结果。