Preconditioning Donor Lungs with Lung-Derived Exosomes Mitigates Ischemia-Reperfusion Injury in a Warm Ischemia Porcine DCD Model.

Abstract

Background: Donation after circulatory death (DCD) donors remains an underutilized source in the U.S due to concerns of ischemia-reperfusion injury (IRI) after prolonged ischemic times. Lung-derived exosomes have shown potential in mitigating pulmonary fibrosis by promoting lung repair. Here, we sought to investigate the potential of lung-derived exosomes to prevent and repair lung IRI.

Methods: We used a porcine DCD model to induce lung injury. Following the determination of optimal warm ischemic time (WIT), donor pigs were allocated into three study groups (n=5, each): control, pre-DCD exosome treatment, and post-DCD exosomes treatment. Lungs were assessed using ex-vivo lung perfusion (EVLP) for functional parameters, histological evaluation, and molecular analysis of inflammatory markers and oxidative stress.

Results: A 1-hour WIT induced consistent lung injury, which was ameliorated with pre-DCD exosome treatment exhibiting significantly improved lung function during EVLP compared to controls. This group presented higher pO2, better lung compliance, lower airway pressures, and reduced pulmonary vascular resistance. Histological analysis indicated reduced edema, vascular congestion, and leukocyte infiltration. Key inflammatory cytokines such as IL-6, IL-1β, TNF-α were significantly downregulated, and reactive oxygen species (ROS) levels were lower than controls. Despite inferior response compared to pre-DCD treatment, post-DCD exosomes treatment also improved lung function and reduced edema formation, with significant decrease in TNF-α expression.

Conclusions: Lung-derived exosome therapy significantly mitigates IRI in a porcine DCD model, improving lung function and reducing inflammation and oxidative stress. These findings support the potential of exosome therapy to increase donor lung utilization, warranting further mechanistic and clinical studies.