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.

摘要