The effect of rewarming ischemia on tissue transcriptome and metabolome signatures: A clinical observational study in lung transplantation.

Paul De Leyn, Arne Neyrinck, Yanina Jansen, Lieven Depypere, Anton Willems, An-Lies Provoost, Ismail Cenik, Christelle M Vandervelde, Simon Feys, Phéline Kortleven, Annalisa Barbarossa, Elena Prisciandaro, Jan Van Slambrouck, Xin Jin, Birgit Weynand, Jacques Pirenne, Laurens J Ceulemans, Geert Carmeliet, Karen Moermans, Shauni Loopmans, Robin Vos, Dirk Van Raemdonck, Hans Van Veer, Johan Van Weyenbergh, Steffen Fieuws, Bart Ghesquière, Bart Vanaudenaerde

Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2025;44(3):437-447

PMID: 39486771

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

In lung transplantation (LuTx), various ischemic phases exist, yet the rewarming ischemia time (RIT) during implantation has often been overlooked. During RIT, lungs are deflated and exposed to the body temperature in the recipient's chest cavity. Our prior clinical findings demonstrated that prolonged RIT increases the risk of primary graft dysfunction. However, the molecular mechanisms of rewarming ischemic injury in this context remain unexplored. We aimed to characterize the rewarming ischemia phase during LuTx by measuring organ temperature and comparing transcriptome and metabolome profiles in tissue obtained at the end versus the start of implantation.

METHODS

In a clinical observational study, 34 double-LuTx with ice preservation were analyzed. Lung core and surface temperature (n = 65 and 55 lungs) were measured during implantation. Biopsies (n = 59 lungs) were wedged from right middle lobe and left lingula at start and end of implantation. Tissue transcriptomic and metabolomic profiling were performed.

RESULTS

Temperature increased rapidly during implantation, reaching core/surface temperatures of 21.5°C/25.4°C within 30 minutes. Transcriptomics showed increased proinflammatory signaling and oxidative stress at the end of implantation. Upregulation of NLRP3 and NFKB1 correlated with RIT. Metabolomics indicated elevated levels of amino acids, hypoxanthine, uric acid, and cysteineglutathione disulfide alongside decreased levels of glucose and carnitines. Arginine, tyrosine, and 1-carboxyethylleucine showed a correlation with incremental RIT.

CONCLUSIONS

The final rewarming ischemia phase in LuTx involves rapid organ rewarming, accompanied by transcriptomic and metabolomic changes indicating proinflammatory signaling and disturbed cell metabolism. Limiting implantation time and cooling of the lung represent potential interventions to alleviate rewarming ischemic injury.

Address: Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.; Department of Cellular and Molecular Medicine, Laboratory of Applied Mass Spectrometry, KU Leuven, Leuven, Belgium; Center for Cancer Biology, Metabolomics Core Facility Leuven, VIB, Leuven, Belgium.; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium; Department of Pharmaceutical and Pharmacological Sciences, Molecular Virology and Gene Therapy, KU Leuven, Leuven, Belgium.; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Infectious and Inflammatory Disorders, KU Leuven, Leuven, Belgium; Department of Medical Intensive Care, University Hospitals Leuven, Leuven, Belgium.; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.; Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium.; Department of Chronic Diseases and Metabolism, Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.; Department of Public Health, Interuniversity Center for Biostatistics and Statistical Bioinformatics, KU Leuven, Leuven, Belgium.; Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium; Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium.; Department of Cardiovascular Sciences, Anesthesiology and Algology, KU Leuven, Leuven, Belgium; Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium.; Department of Pathology, University Hospitals Leuven, Leuven, Belgium; Department of Imaging and Pathology, Laboratory of Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium.; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium.; Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium. Electronic address: [email protected].

DOI: 10.1016/j.healun.2024.10.020

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MeSH Terms: Humans, Lung Transplantation, Male, Female, Metabolome, Middle Aged, Transcriptome, Adult, Rewarming, Lung, Organ Preservation