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

Autor:	Wang A; Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada., Ali A; Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada., Baciu C; Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada., Bellissimo C; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada., Siebiger G; Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada., Yamanashi K; Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada., Montagne J; Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada., Garza G; Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada., Goligher E; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada., Keshavjee S; Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada; Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada., Liu M; Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada., Cypel M; Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada; Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada. Electronic address: marcelo.cypel@uhn.ca.
Jazyk:	angličtina
Zdroj:	The Journal of thoracic and cardiovascular surgery [J Thorac Cardiovasc Surg] 2024 Aug 22. Date of Electronic Publication: 2024 Aug 22.
DOI:	10.1016/j.jtcvs.2024.08.015
Abstrakt:	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 were 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 was performed to test for the separability of the paired samples. Significantly changed metabolites between the 2 time points 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), principal component analysis 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 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. Conclusions: 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. Competing Interests: Conflict of Interest Statement M.C., M.L., and S.K. are shareholders of Traferox Technologies Inc. S.K. serves as Chief Medical Officer of Traferox Technologies Inc, receives personal fees from Traferox Technologies Inc, and is an inventor of IP licensed to Traferox Technologies Inc. M.C. serves as Chief Scientific Officer of Traferox Technologies Inc, receives personal fees from Traferox Technologies Inc, and is an inventor of IP licensed to Traferox Technologies Inc. Traferox devices were not used in any part of the study. M.C. and S.K. are consultants for Lung Bioengineering Inc. S.K. is a consultant for Abbott, CareDx, and United Therapeutics. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu