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: 10227245
• 负责人: Nahmah Kim-Campbell
• 金额: $ 15.99万
• 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/10227245
• 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.

抽象的 多年来，小儿心脏手术中的体外循环 (CPB) 已得到完善，但 不良后果，例如急性肾损伤 (AKI)，这与死亡率和长期 ICU 相关 和住院时间，仍然存在问题且不完全了解。无细胞血浆血红蛋白 (PHb) 在 CPB 和其他形式的体外治疗过程中可能会大量产生。终极 该提案的重点是促进对病理生理学和作用机制的了解 CPB 后 AKI 中的 PHb 以确定有临床意义的治疗方法。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，同时也试图有一个更机械化的方法 使用体外治疗的体内啮齿动物模型来定义潜在治疗靶点的方法。 初步数据表明，接受 CPB 的儿童中 PHb 与 AKI 的相关性与年龄和年龄有关。 性别相关差异，并与一氧化氮 (NO) 生物利用度降低和增加有关 氧化应激指标。最近的初步数据还表明，脂质氧化的最终产物（9 和 13-羟基十八碳二烯酸 [HODE]）具有生物活性，导致对血管活性物质的需求增加 药物。该提案重点关注 PHb 和 PHb-触珠蛋白复合物具有过氧化物酶的观点 消耗还原剂或抗氧化剂的活动，例如抗坏血酸、谷胱甘肽和一氧化氮 (NO) 以及 也导致 HODE 的产生。这些氧化应激的生化指标将在 人类和大鼠样本。 HODE 的生物活性、NO 生物利用度的变化以及 NO 的消耗 抗氧化剂会导致功能性影响（通过血管活性药物的需要、肾血的变化来评估 流量和肾功能）和肾损伤的组织学证据。体外啮齿动物模型的使用 治疗将允许侵入性测量肾血流量、体内 NO 可用性以及评估能力 肾脏组织学。在这个实验模型中引入了有针对性的干预措施，即亚硝酸盐，一种NO 供体和 MnPP，消除超氧化物及其歧化产物 H2O2（过氧化物酶的燃料） 活性），因此有望改善肾损伤。 该提议将提高识别 CPB 后 PHb 介导的肾损伤危险因素的能力 并阐明 PHb 驱动 AKI 的机制。 Kim-Campbell 博士组建了一个指导团队 由氧化应激和自由基专家 Hülya Bayır 博士领导的国际知名研究人员组成 生物学。可用的资源、机构支持和卓越的指导环境将为博士提供帮助。 Kim-Campbell 拥有成为一名独立临床科学家的基础，具有有意义的专业知识 改善体外治疗中肾脏不良结局的机械支持方法。