Sun Xiangfu, Huang Ai, Zhang Huan, Song Naicheng, Huang Zhihong, Xin Gaojie, Wang Zhaokai, Liu Mingyao, Jiang Ke, Huang Lei
Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
Transplantation. 2025 Feb 1;109(2):319-331. doi: 10.1097/TP.0000000000005144. Epub 2025 Jan 20.
Concern of ischemia-reperfusion injury reduces utilization of donor lungs. We hypothesized adding L-alanyl-L-glutamine (L-AG) to preservation solution may protect donor lungs from ischemia-reperfusion injury through its multiple cytoprotective effects.
A lung transplantation cell culture model was used on human lung epithelial cells and pulmonary microvascular endothelial cells, and the effects of adding different concentrations of L-AG on basic cellular function were tested. Rat donor lungs were preserved at 4 °C with 8 mmol/L L-AG for 12 h followed by 4 h reperfusion or monitored for 3 d. Lung function, lung histology, inflammation, and cell death biomarker were tested. Computerized tomography scan was used and metabolomic analysis was performed on lung tissues.
Cold preservation with L-AG improved cell viability and inhibited apoptosis in cell culture. Rat donor lungs treated with L-AG during cold storage showed decreased peak airway pressure, higher dynamic compliance and oxygenation ability, reduced lung injury, apoptosis, and oxidative stress during reperfusion. L-AG treatment significantly changed 130 metabolites during reperfusion, with enhanced amino acid biosynthesis and tricarboxylic acid cycle. Furthermore, cold storage with L-AG decreased primary graft dysfunction grade, improved oxygenation, reduced pulmonary atelectasis, sign of infection, and pneumothorax in a rat left lung transplant 3-d survival model.
Adding L-AG to cold preservation solution reduced lung injury and alleviated primary graft dysfunction by inhibiting inflammation, oxidative stress, and cell death with modified metabolic activities.
对缺血再灌注损伤的担忧降低了供体肺的利用率。我们假设在保存液中添加L-丙氨酰-L-谷氨酰胺（L-AG）可能通过其多种细胞保护作用保护供体肺免受缺血再灌注损伤。
在人肺上皮细胞和肺微血管内皮细胞上使用肺移植细胞培养模型，测试添加不同浓度L-AG对基本细胞功能的影响。将大鼠供体肺在4℃下用8 mmol/L L-AG保存12小时，然后再灌注4小时或监测3天。测试肺功能、肺组织学、炎症和细胞死亡生物标志物。使用计算机断层扫描并对肺组织进行代谢组学分析。
L-AG冷保存提高了细胞活力并抑制了细胞培养中的细胞凋亡。冷藏期间用L-AG处理的大鼠供体肺在再灌注期间显示气道峰值压力降低、动态顺应性和氧合能力更高、肺损伤、细胞凋亡和氧化应激减少。L-AG处理在再灌注期间显著改变了130种代谢物，增强了氨基酸生物合成和三羧酸循环。此外，在大鼠左肺移植3天存活模型中，L-AG冷保存降低了原发性移植功能障碍等级，改善了氧合，减少了肺不张、感染迹象和气胸。
在冷保存液中添加L-AG可通过抑制炎症、氧化应激和细胞死亡并改变代谢活动来减少肺损伤并减轻原发性移植功能障碍。
