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
{"title":"The effect of rewarming ischemia on tissue transcriptome and metabolome signatures: A clinical observational study in lung transplantation.","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":15900,"journal":{"name":"Journal of Heart and Lung Transplantation","volume":" ","pages":""},"PeriodicalIF":6.4000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Heart and Lung Transplantation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.healun.2024.10.020","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
The Journal of Heart and Lung Transplantation, the official publication of the International Society for Heart and Lung Transplantation, brings readers essential scholarly and timely information in the field of cardio-pulmonary transplantation, mechanical and biological support of the failing heart, advanced lung disease (including pulmonary vascular disease) and cell replacement therapy. Importantly, the journal also serves as a medium of communication of pre-clinical sciences in all these rapidly expanding areas.