Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
J Transl Med. 2024 Mar 1;22(1):221. doi: 10.1186/s12967-024-05024-x.
Cellular stress associated with static-cold storage (SCS) and warm reperfusion of donor lungs can contribute to ischemia-reperfusion (IR) injury during transplantation. Adding cytoprotective agents to the preservation solution may be conducive to reducing graft deterioration and improving post-transplant outcomes.
SCS and warm reperfusion were simulated in human lung epithelial cells (BEAS-2B) by exposing cells to low potassium dextran glucose solution at 4 °C for different periods and then switching back to serum-containing culture medium at 37 °C. Transcriptomic analysis was used to explore potential cytoprotective agents. Based on its results, cell viability, caspase activity, cell morphology, mitochondrial function, and inflammatory gene expression were examined under simulated IR conditions with or without thyroid hormones (THs).
After 18 h SCS followed by 2 h warm reperfusion, genes related to inflammation and cell death were upregulated, and genes related to protein synthesis and metabolism were downregulated in BEAS-2B cells, which closely mirrored gene profiles found in thyroid glands of mice with congenital hypothyroidism. The addition of THs (T3 or T4) to the preservation solution increases cell viability, inhibits activation of caspase 3, 8 and 9, preserves cell morphology, enhances mitochondrial membrane potential, reduces mitochondrial superoxide production, and suppresses inflammatory gene expression.
Adding THs to lung preservation solutions may protect lung cells during SCS by promoting mitochondrial function, reducing apoptosis, and inhibiting pro-inflammatory pathways. Further in vivo testing is warranted to determine the potential clinical application of adding THs as therapeutics in lung preservation solutions.
与静态冷藏（SCS）和供体肺的温热再灌注相关的细胞应激会导致移植过程中的缺血再灌注（IR）损伤。在保存液中添加细胞保护剂可能有利于减少移植物恶化并改善移植后的结果。
通过将细胞暴露于 4°C 的低钾葡聚糖葡萄糖溶液中不同时间，然后再切换回 37°C 的含血清培养基来模拟 SCS 和温热再灌注。转录组分析用于探索潜在的细胞保护剂。基于其结果，在模拟 IR 条件下，检查了有无甲状腺激素（THs）时细胞活力、半胱天冬酶活性、细胞形态、线粒体功能和炎症基因表达。
在 SCS 18 小时后再灌注 2 小时，BEAS-2B 细胞中与炎症和细胞死亡相关的基因上调，与蛋白质合成和代谢相关的基因下调，这与先天性甲状腺功能减退症小鼠甲状腺中的基因谱非常相似。将 TH（T3 或 T4）添加到保存溶液中可增加细胞活力，抑制半胱天冬酶 3、8 和 9 的激活，保持细胞形态，增强线粒体膜电位，减少线粒体超氧化物产生，并抑制炎症基因表达。
在 SCS 期间向肺保存液中添加 TH 可能通过促进线粒体功能、减少细胞凋亡和抑制促炎途径来保护肺细胞。需要进一步的体内测试来确定在肺保存液中添加 TH 作为治疗剂的潜在临床应用。
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