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

基本信息

批准号：
10431493
负责人：
Lorraine B Ware
金额：
$ 48.63万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10431493
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 Clinical Clinical Management Clinical Trials Cohort Studies Critical Illness Data Development Endothelium Epithelial 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 of activation protein Microvascular Permeability Modeling Molecular Outcome Patients Pattern Perfusion Perioperative Permeability Pilot Projects Plasma Cells Practice Pattern Variations Publishing Pulmonary Edema Reperfusion Therapy Risk Risk Factors 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

项目摘要

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，20-30% 的肺移植受者出现原发性移植物功能障碍并且是短期和长期结果的主要决定因素。 PGD 风险受临床特征影响捐赠者和接受者双方以及操作管理。然而，细胞机制 PGD 的潜在风险尚未完全了解，对 PGD 机制的新研究正在进行中对于开发和测试降低 PGD 风险的特定疗法至关重要。我们已发布的和初步的数据表明，无细胞血红蛋白（CFH）是肺泡毛细血管破坏的主要致病因素，导致 PGD 中肺水肿的特征性发展。在一项试点病例对照研究中，我们表明受者术前血浆 CFH 升高与 PGD 风险增加独立相关。在一个人离体肺灌注模型，灌注液中的CFH通过以下方式引起微血管通透性增加肺内皮细胞氧化损伤。同样，肺泡内 CFH 水平升高与危重病人严重肺损伤和CFH支气管内滴注离体人肺损伤肺上皮屏障并损害肺泡液清除率。新的初步数据显示 CFH 增加供体肺同种异体移植物的空域。在本提案中，我们将确定围手术期管理如何放大CFH对PGD的影响。体外循环（CPB）和体外膜氧合 (ECMO) 会增加溶血和 CFH 的释放。尽管 ECMO 已与 PGD 风险低于 CPB，但尚不清楚这是否可以通过 CFH 的改变来解释。更高的驱动压力机械通气期间也可能增加 CFH 和肺泡毛细血管屏障功能障碍。此外，再灌注时 FiO2 增加会增强 CFH 和 PGD 之间的关联，并且高氧会加剧 CFH 在离体人肺中引起的肺损伤。这一强有力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。在这个提案中，我们将建立一个三中心联盟来检验 CFH 通过氧化损伤导致 PGD 的假设肺内皮和上皮屏障。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积累和氧化 CFH，从而增加 PGD 的风险。有三个具体目标：1）测试独立效果血管内和肺泡内 CFH 对 PGD 风险以及内皮和上皮屏障损伤的影响，2) 确定围手术期因素如何影响血管内和肺泡内 CFH 积聚，以及 3) 测试如何影响术中高氧引起的 CFH 氧化会增加 PGD 的风险。完成这一大型多中心队列研究对肺移植受者的研究将为了解血管内和肺移植的相对贡献提供新的见解。肺泡内 CFH 到 PGD 并确定改变 CFH 积累和氧化的可修改因素，提供为开展临床试验提供必要的基础，以通过针对 CFH 的干预措施来减轻 PGD。