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

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

doi:10.1016/j.healun.2024.10.020

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

J Heart Lung Transplant. 2024 Oct 30:S1053-2498(24)01905-3. doi: 10.1016/j.healun.2024.10.020. Online ahead of print.

Authors

Jan Van Slambrouck¹, Shauni Loopmans², Elena Prisciandaro¹, Annalisa Barbarossa¹, Phéline Kortleven³, Simon Feys⁴, Christelle M Vandervelde¹, Xin Jin⁵, Ismail Cenik⁶, Karen Moermans⁷, Steffen Fieuws⁸, An-Lies Provoost¹, Anton Willems², Paul De Leyn¹, Hans Van Veer¹, Lieven Depypere¹, Yanina Jansen¹, Jacques Pirenne⁹, Arne Neyrinck¹⁰, Birgit Weynand¹¹, Bart Vanaudenaerde⁵, Geert Carmeliet⁷, Robin Vos¹², Dirk Van Raemdonck¹, Bart Ghesquière², Johan Van Weyenbergh¹³, Laurens J Ceulemans¹⁴

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.
⁶ Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium.
⁷ Department of Chronic Diseases and Metabolism, Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
⁸ Department of Public Health, Interuniversity Center for Biostatistics and Statistical Bioinformatics, KU Leuven, Leuven, Belgium.
⁹ Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium; Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium.
¹⁰ Department of Cardiovascular Sciences, Anesthesiology and Algology, KU Leuven, Leuven, Belgium; Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium.
¹¹ Department of Pathology, University Hospitals Leuven, Leuven, Belgium; Department of Imaging and Pathology, Laboratory of Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium.
¹² 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.
¹³ Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium.
¹⁴ 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].

PMID: 39486771
DOI: 10.1016/j.healun.2024.10.020

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.

Keywords: anastomosis; ischemia; lung transplantation; metabolomics; transcriptomics.