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.

中文翻译：

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复温缺血对组织转录组和代谢组特征的影响：肺移植的临床观察研究。


背景 在肺移植 （LuTx） 中，存在各种缺血期，但植入过程中的复温缺血时间 （RIT） 经常被忽视。在 RIT 期间，肺部放气并暴露在受者胸腔中的体温下。我们之前的临床发现表明，延长的 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，再复温缺血性损伤的分子机制仍未得到探索。我们旨在通过测量器官温度并比较植入结束时与植入开始时获得的组织中的转录组和代谢组谱来表征 LuTx 期间的复温缺血阶段。方法 在一项临床观察研究中，分析了 34 例冰保存的双 LuTx。植入期间测量肺核心和肺表面温度 （n=65 和 55 肺）。活检 （n=59 个肺） 在植入开始和结束时从右中叶和左舌骨楔入。进行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，在 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。代谢组学表明氨基酸、次黄嘌呤、尿酸、二硫化半胱氨酸谷胱甘肽水平升高，同时葡萄糖和肉碱水平降低。精氨酸、酪氨酸和 1-羧乙基亮氨酸与增量 RIT 相关。结论 LuTx 的最后复温缺血阶段涉及快速器官复温，伴有转录组学和代谢组学变化，表明促炎信号传导和细胞代谢紊乱。 限制植入时间和肺降温是减轻复温缺血损伤的潜在干预措施。