Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: Lungs perfused with modified Steen showed reduced pulmonary vascular resistance (p = 0.0391) and stable pulmonary artery pressure despite achieving higher flows (p = 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 (p = 0.0040) in modified Steen compared to Steen. Recipients of lungs perfused with modified Steen also showed improved post-transplantation oxygenation (p = 0.0462). CONCLUSIONS: 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.