Metabolomic studies reveal an organ-protective hibernation state in donor lungs preserved at 10°C.

ABSTRACT

OBJECTIVE: Previous reports showed enhanced graft function in both healthy and injured porcine lungs after preservation at 10°C. The objective of the study is to elucidate the mechanism of lung protection by 10°C and identify potential therapeutic targets to improve organ preservation. METHODS: Metabolomics data was analyzed from healthy and injured porcine lungs that underwent extended hypothermic preservation on ice and at 10°C. Tissue sampled before and after preservation were subjected to untargeted metabolic profiling. Principal component analysis (PCA) was performed to test for the separability of the paired samples. Significantly changed metabolites between the two timepoints were identified and analyzed to determine the underlying metabolic pathways. The levels of respiratory activity of lung tissue at hypothermic temperatures were confirmed using high resolution respirometry. RESULTS: In both healthy and injured lungs (n=5 per intervention), PCA suggested minimal change in metabolites after ice preservation, but significant change of metabolites after 10°C preservation, which was associated with significantly improved lung function as assessed by ex vivo lung perfusion (EVLP) and lung transplantation. For healthy lungs, lipid energy pathway was found primarily active at 10°C. For injured lungs, additional carbohydrate energy pathway and anti-ferroptosis pathways aiding organ repair were identified. These metabolic features are also key features involved in mammal hibernation. CONCLUSION: Untargeted metabolomics revealed a dynamic metabolic gradient for lungs stored at 10°C. Elucidating the underlying mechanisms behind this pathway regulation may lead to strategies that will allow organs "hibernate" for days, potentially making organ banking a reality.