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: 10438683
• 负责人: Nahmah Kim-Campbell
• 金额: $ 15.95万
• 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/10438683
• 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; lipidomics; 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.

摘要 多年来，小儿心脏手术中的心脏搭桥术（CPB）已得到改进，但 不利的结局，如急性肾损伤（阿基），与死亡率和ICU延长相关 和住院时间，仍然存在问题和不完全理解。细胞游离血浆血红蛋白 (PHb)可在CPB和其他形式的体外治疗期间大量产生。最终 这项建议的重点是有助于了解的病理生理学和机制的作用， CPB后阿基中的PHb，以确定具有临床意义的治疗。本提案的研究计划 旨在通过一项前瞻性临床研究来检验这一点，同时也试图进行更机械的研究。 使用体外治疗的体内啮齿动物模型确定潜在治疗靶点的方法。 初步数据表明，在接受CPB的儿童中，随着年龄的增长， 与性别相关的差异，并与降低一氧化氮（NO）的生物利用度和增加 氧化应激的指标。最近的初步数据还显示，脂质氧化的终产物（9和10）在脂质代谢中起重要作用。 13-羟基十八碳二烯酸[HODE]）可以是生物活性的，并导致对血管活性物质的需求增加 药物治疗该建议的重点是这样的想法，即PHb和PHb-触珠蛋白复合物具有过氧化物酶 活动消耗还原剂或抗氧化剂，如抗坏血酸，谷胱甘肽和一氧化氮（NO）， 也导致HODE的产生。这些氧化应激的生化指标将在 人类和老鼠的样本。HODE的生物活性，NO生物利用度的变化，以及 抗氧化剂将导致功能效应（通过对血管活性药物的需要、肾血的变化来评估 血流和肾功能）和肾损伤的组织学证据。使用啮齿类动物体外循环模型 治疗将允许侵入性测量肾血流量、体内NO可用性和评估 肾脏组织学在这个实验模型中引入有针对性的干预措施，即亚硝酸盐，一种NO 供体和MnPP，其消除超氧化物及其歧化产物H2 O2（过氧化物酶的燃料 活性），因此预期改善肾损伤。 这一建议将导致更大的能力，以确定CPB后的PHb介导的肾损伤的危险因素 并阐明PHb驱动阿基的机制。金·坎贝尔博士组建了一个指导小组 由氧化应激和自由基专家Hülya Bayır博士领导的国际公认的研究人员 生物学可用的资源，机构的支持，和特殊的指导环境将提供博士。 金坎贝尔与基金会成为一个独立的临床科学家与专业知识，在有意义的 改善体外治疗中不良肾脏结局的机械支持方法。