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

IF 6.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Journal of Heart and Lung Transplantation Pub Date : 2024-10-30 DOI:10.1016/j.healun.2024.10.020

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

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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) was 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 30min. Transcriptomics showed increased pro-inflammatory 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, cysteineglutathione disulfide alongside decreased levels of glucose and carnitines. Arginine, tyrosine, and 1-carboxyethylleucine showed correlation with incremental RIT.

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

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复温缺血对组织转录组和代谢组特征的影响：肺移植临床观察研究。

背景：在肺移植（LuTx）中，存在各种缺血阶段，但植入过程中的复温缺血时间（RIT）往往被忽视。在 RIT 期间，肺被放气并暴露在受者胸腔内的体温下。我们之前的临床研究结果表明，延长 RIT 会增加原发性移植物功能障碍的风险。然而，在这种情况下，回温缺血性损伤的分子机制仍有待探索。我们的目的是通过测量器官温度和比较植入结束时与开始时获得的组织中的转录组和代谢组特征，来描述 LuTx 期间的复温缺血阶段：在一项临床观察研究中，分析了 34 例采用冰保存的双 LuTx。在植入过程中测量了肺核心和表面温度（分别为 65 肺和 55 肺）。在植入开始和结束时，从右肺中叶和左肺楔取活检组织（n=59）。进行了组织转录组学和代谢组学分析：结果：植入过程中温度迅速升高，30 分钟内达到 21.5°C/25.4°C 的核心/表面温度。转录组学显示，植入结束时促炎症信号传导和氧化应激增加。NLRP3 和 NFKB1 的上调与 RIT 相关。代谢组学显示氨基酸、次黄嘌呤、尿酸、半胱氨酸谷胱甘肽二硫化物水平升高，葡萄糖和肉碱水平下降。精氨酸、酪氨酸和 1-羧乙基亮氨酸与 RIT 增量相关：结论：LuTx 最后的复温缺血阶段涉及器官的快速复温，伴随着转录组和代谢组的变化，表明存在促炎信号传导和细胞代谢紊乱。限制植入时间和肺部冷却是减轻复温缺血损伤的潜在干预措施。

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来源期刊

Journal of Heart and Lung Transplantation 医学-呼吸系统

CiteScore

10.10

自引率

6.70%

发文量

1667

审稿时长

69 days

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.