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

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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.