Peri-operative factors that drive cell-free hemoglobin-mediated primary graft dysfunction

驱动无细胞血红蛋白介导的原发性移植物功能障碍的围手术期因素

• 批准号: 10677593
• 负责人: Lorraine B Ware
• 金额: $ 46.35万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677593
• 关键词: Acute Lung Injury; Affect; Alveolar; Alveolar Cell; Automobile Driving; Biological Markers; Blood Circulation; Blood capillaries; Cardiopulmonary Bypass; Caring; Case/Control Studies; Cells; Characteristics; Circulation; Clinical; Clinical Management; Clinical Trials; Cohort Studies; Critical Illness; Data; Development; Endothelium; Epithelium; Extracorporeal Membrane Oxygenation; Foundations; Functional disorder; Geography; Hemoglobin; Hemoglobin concentration result; Hemolysis; Human; Hyperoxia; Impairment; Injury; Intervention; Lipid Peroxidation; Liquid substance; Lung; Lung Transplantation; Measures; Mechanical ventilation; Mechanics; Mediating; Mediator; Microvascular Permeability; Modeling; Molecular; Outcome; Patients; Pattern; Perfusion; Perioperative; Permeability; Pilot Projects; Plasma; Plasma Cells; Practice Pattern Variations; Publishing; Pulmonary Edema; Reperfusion Therapy; Risk; Risk Factors; Risk Reduction; Role; Severities; Site; Testing; Therapeutic Clinical Trial; Translations; Transplant Recipients; clinical development; clinical practice; clinically relevant; graft dysfunction; insight; lung allograft; lung injury; modifiable risk; novel; oxidation; oxidative damage; pressure; translational study; transplant centers

Primary graft dysfunction, a severe form of acute lung injury, occurs in 20-30% of lung transplant recipients and is a major determinant of both short- and long-term outcomes. Risk of PGD is affected by clinical features of both the donor and recipient as well as by operative management. However, the cellular mechanisms that underlie risk of PGD are incompletely understood and new studies of mechanisms contributing to PGD are essential to development and testing of specific therapies to mitigate PGD risk. Our published and preliminary data suggest that cell-free hemoglobin (CFH) is a major causal factor in the alveolar-capillary disruption that leads to the characteristic development of pulmonary edema in PGD. In a pilot case-control study, we showed that elevated recipient pre-operative plasma CFH is independently associated with increased PGD risk. In a human ex vivo lung perfusion model, CFH in the perfusate caused increased microvascular permeability by oxidative injury to the lung endothelium. Similarly, elevated levels of intra-alveolar CFH are associated with severe lung injury in critically ill patients and intra-bronchial instillation of CFH into ex vivo human lungs injures the lung epithelial barrier and impairs alveolar fluid clearance. New preliminary data show increased CFH in the airspace of donor lung allografts. In this proposal, we will determine how peri-operative management may magnify the impact of CFH on PGD. Cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) increase hemolysis and release of CFH. Although ECMO has been associated with lower PGD risk than CPB, it is unclear whether this is explained by alterations in CFH. Higher driving pressure during mechanical ventilation may also increase CFH and alveolar-capillary barrier dysfunction. Furthermore, increased FiO2 at reperfusion augments the association between CFH and PGD and hyperoxia exacerbates CFH-induced lung injury in ex vivo human lungs. This strong preliminary data supports the concept that peri- operative management affects PGD by modulating accumulation and oxidation of CFH. In this proposal, we will establish a three-site consortium to test the hypothesis that CFH causes PGD via oxidative injury to the lung endothelial and epithelial barriers. We will also determine how modifiable risk factors including mechanical support and hyperoxia at reperfusion increase accumulation and oxidation of CFH, thereby increasing risk of PGD. There are three specific aims: 1) test the independent effects of intravascular and intra-alveolar CFH on risk of PGD and injury to the endothelial and epithelial barriers, 2) determine how peri-operative factors affect intravascular and intra-alveolar CFH accumulation, and 3) test how CFH oxidation by intra-operative hyperoxia increases risk of PGD. Completion of this large multicenter cohort study of lung transplant recipients will provide novel insight into the relative contributions of intravascular and intra-alveolar CFH to PGD and identify modifiable factors that alter CFH accumulation and oxidation, providing the necessary foundation for development of clinical trials to mitigate PGD with CFH-targeted interventions.

原发性移植物功能障碍是一种严重的急性肺损伤，发生在20-30%的肺移植受者中