Gilmour Jenny, Sigvardsson Anne-Li, Henriksson Emilia, Fisher Andrew J, Ali Simi
Newcastle University Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
XVIVO Perfusion AB, Gothenburg, Sweden.
JHLT Open. 2024 Apr 2;4:100091. doi: 10.1016/j.jhlto.2024.100091. eCollection 2024 May.
Ex vivo lung perfusion allows donor lung preservation, assessment, and reconditioning before transplantation, but is associated with increased inflammatory injury over time. Addition of antioxidative and anti-inflammatory agents to perfusate formulations could limit iatrogenic injury during perfusion. The effectiveness of a modified Steen solution containing acetyl salicylic acid, retinoic acid, and methylprednisolone was examined using a porcine extended criteria donor ex vivo lung perfusion and transplantation model.
Porcine donor lungs underwent 24 hours cold storage and were then randomized to 4 hours normothermic ex vivo lung perfusion with modified Steen or original Steen, followed by single lung transplantation into a recipient pig. RNA-sequencing was used to assess tissue inflammatory changes during perfusion. Organ function was examined during perfusion and following transplantation and compared between groups.
Lungs perfused with modified Steen showed reduced pulmonary vascular resistance ( = 0.0391) and stable pulmonary artery pressure despite achieving higher flows ( = 0.0001) compared to Steen. Lung tissue showed negative enrichment of the tumor necrosis factor-α (TNF-α) signaling via nuclear factor-κB (NF-κB) pathway ( = 0.0040) in modified Steen compared to Steen. Recipients of lungs perfused with modified Steen also showed improved post-transplantation oxygenation ( = 0.0462).
This study highlights the superiority of modified Steen compared with original Steen. The modifications to Steen solution appear to limit inflammatory injury via the NF-κB signaling pathway during perfusion, leading to improved post-transplant function. Modified Steen provides the potential to improve post-transplant outcomes following ex vivo lung perfusion of extended criteria lungs and could also facilitate extended assessment and preservation, as well as administration of advanced therapies.
体外肺灌注可在移植前对供体肺进行保存、评估和修复，但随着时间的推移会增加炎症损伤。在灌注液配方中添加抗氧化和抗炎药物可能会限制灌注过程中的医源性损伤。使用猪扩大标准供体体外肺灌注和移植模型，研究了含乙酰水杨酸、视黄酸和甲泼尼龙的改良Steen溶液的有效性。
猪供体肺经历24小时冷保存，然后随机分为两组，分别用改良Steen溶液或原始Steen溶液进行4小时常温体外肺灌注，随后将单肺移植到受体猪体内。采用RNA测序评估灌注过程中的组织炎症变化。在灌注期间和移植后检查器官功能，并在组间进行比较。
与Steen溶液相比，用改良Steen溶液灌注的肺尽管流量更高（P = 0.0001），但肺血管阻力降低（P = 0.0391），肺动脉压稳定。与Steen溶液相比，改良Steen溶液灌注的肺组织显示肿瘤坏死因子-α（TNF-α）通过核因子-κB（NF-κB）途径的信号负富集（P = 0.0040）。接受改良Steen溶液灌注肺的受体移植后的氧合也有所改善（P = 0.0462）。
本研究突出了改良Steen溶液相对于原始Steen溶液的优越性。对Steen溶液的改良似乎在灌注过程中通过NF-κB信号通路限制了炎症损伤，从而改善了移植后的功能。改良Steen溶液有可能改善扩大标准肺体外肺灌注后的移植结局，还可促进延长评估和保存以及先进治疗的应用。
