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.

一级移植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 并且是短期和长期结局的主要决定因素。 PGD​​风险受临床特征的影响 捐助者和接收者以及手术管理中都有但是，细胞机制 PGD​​风险的基础尚不完全了解，对PGD造成PGD的机制的新研究是 对特定疗法的开发和测试至关重要，以减轻PGD风险。我们出版和初步 数据表明，无细胞血红蛋白（CFH）是肺泡毛细血管破坏的主要因果因素 导致PGD中肺水肿的特征发展。在一项试点案例对照研究中，我们表明 较高的受体术前等离子体CFH与PGD风险增加有关。在 人体体内肺灌注模型，灌注液中的CFH导致微血管渗透性增加 肺内皮氧化损伤。同样，肺泡内CFH水平升高与 重症患者的严重肺损伤和将CFH机管内输入体内人肺损伤 肺上皮屏障并损害肺泡流体清除率。新的初步数据显示CFH在 供体肺同种异体移植物的空间。在此提案中，我们将确定围手术管理如何 放大CFH对PGD的影响。心肺旁路（CPB）和体外膜 氧合（ECMO）增加CFH的溶血和释放。尽管ECMO与 PGD​​风险低于CPB，目前尚不清楚这是否通过CFH的改变来解释。较高的驾驶压力 在机械通气过程中，还可能增加CFH和肺泡毛细管屏障功能障碍。此外， 再灌注时的FIO2增加了CFH和PGD之间的关联以及高氧加剧 CFH诱导的肺部肺部肺部肺损伤。这个强大的初步数据支持了以下概念 手术管理通过调节CFH的积累和氧化来影响PGD。在这个建议中，我们 将建立一个三个站点联盟，以测试CFH通过氧化损伤引起PGD的假设。 到肺内皮和上皮屏障。我们还将确定如何改变风险因素 包括机械支持和再灌注时的高氧增加增加积累和氧化的氧化 CFH，从而增加了PGD的风险。有三个具体目的：1）测试 血管内和肺泡内CFH在PGD风险以及内皮和上皮屏障的风险下，2） 确定围手术因素如何影响血管内和肺泡内CFH积累，3）测试如何 通过术中高氧CFH氧化会增加PGD的风险。完成这个大型多中心队列 肺移植受者的研究将提供对血管内和血管内相对贡献的新见解。 肺泡内CFH至PGD并确定可改变CFH积累和氧化的可修改因素，从而提供 开发临床试验的必要基础，以通过CFH为目标的干预措施来减轻PGD。