BACKGROUND Ischemia-reperfusion injury (IRI) stands as a major trigger for primary graft dysfunction (PGD) in lung transplantation (LTx). Especially in LTx from donation after cardiac death (DCD), effective control of IRI following warm ischemia (WIRI) is crucial to prevent PGD. This study aimed to identify the key factors affecting WIRI in LTx from DCD. METHODS Previously reported RNA-sequencing dataset of lung WIRI was reanalyzed to identify nuclear receptor subfamily 4 group A member 1 (NR4A1) as the immediate early gene for WIRI. Dynamics of NR4A1 expression were verified using a mouse hilar clamp model. To investigate the role of NR4A1 in WIRI, a mouse model of LTx from DCD was established using Nr4a1 knockout (Nr4a1-/-) mice. RESULTS NR4A1 was located around vascular cells, and its protein levels in the lungs increased rapidly and transiently during WIRI. LTｘ from Nr4a1-/- donors significantly improved pulmonary graft function compared to wild-type donors. Histological analysis showed decreased microvascular endothelial cell death, neutrophil infiltration, and albumin leakage. Evans blue permeability assay demonstrated maintained pulmonary microvascular barrier integrity in grafts from Nr4a1-/- donors, correlating with diminished pulmonary edema. However, NR4A1 did not significantly affect the inflammatory response during WIRI, and IRI was not suppressed when a wild-type donor lung was transplanted into the Nr4a1-/- recipient. CONCLUSIONS Donor NR4A1 plays a specialized role in the positive regulation of endothelial cell injury and microvascular hyperpermeability. These findings demonstrate the potential of targeting NR4A1 interventions to alleviate PGD and improve outcomes in LTx from DCD.

中文翻译：

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Nr4a1 的缺失可改善循环死亡供体肺移植中的内皮细胞损伤和血管渗漏。


背景缺血再灌注损伤 （IRI） 是肺移植 （LTx） 中原发性移植物功能障碍 （PGD） 的主要触发因素。特别是在心源性死亡 （DCD） 后捐献的 LTx 中，有效控制热缺血后 IRI （WIRI） 对于预防 PGD 至关重要。本研究旨在确定影响 DCD 中 LTx 中 WIRI 的关键因素。方法 重新分析先前报道的肺 WIRI RNA 测序数据集，以确定核受体亚家族 4 A 组成员 1 （NR4A1） 是 WIRI 的直接早期基因。使用小鼠肺门夹模型验证 NR4A1 表达的动力学。为了研究 NR4A1 在 WIRI 中的作用，使用 Nr4a1 敲除 （Nr4a1-/-） 小鼠建立了来自 DCD 的 LTx 小鼠模型。结果 NR4A1 位于血管细胞周围，在 WIRI 期间其在肺部的蛋白水平迅速而短暂地升高。与野生型供体相比，来自 Nr4a1-/-供体的 LTx 显着改善了肺移植物功能。组织学分析显示微血管内皮细胞死亡、中性粒细胞浸润和白蛋白渗漏减少。伊文思蓝通透性测定表明，来自 Nr4a1-/-供体的移植物保持了肺微血管屏障完整性，与肺水肿减轻相关。然而，NR4A1 对 WIRI 期间的炎症反应没有显著影响，当野生型供体肺移植到 Nr4a1-/- 受体中时，IRI 没有受到抑制。结论 供体 NR4A1 在内皮细胞损伤和微血管高通透性的正调控中起特殊作用。这些发现证明了靶向 NR4A1 干预以减轻 PGD 和改善 DCD 的 LTx 结果的潜力。