Ex vivo lung perfusion-to-lung transplant rat survival model with reproducible development of acute lung injury and graft rejection

Background

Ex vivo lung perfusion (EVLP) has been clinically applied as a lung preservation and assessment tool prior to lung transplantation (LTx) and is evolving to become a platform to deliver cellular and gene therapies or inactivate pathogens. Here we aimed to investigate the utility of our recently reported rat EVLP-to-LTx model as the smallest ever experimental survival model of EVLP-to-LTx and to compare late graft endpoints between strain combinations.

Methods

We tested three strains as normothermic EVLP donors: Fisher 344 (F344), Lewis (LEW), and Wistar Kyoto (WKy) rats. Then we tested three strain combinations of EVLP-to-LTx (F344-to-WKy, F344-to-LEW, and LEW-to-LEW) to compare histologic and radiologic changes.

Results

F344 and LEW, but not WKy rat lungs, tolerated 4 hours of normothermic EVLP. F344-to-WKy EVLP-to-LTx developed significant histologic (as measured by acute lung injury score, ISHLT A and B grade rejection score) and radiologic (volume and mean Hounsfield units of aerated lung graft analyzed by computed tomography at day 7 after EVLP-to-LTx) changes in the lung allograft. In this strain combination, progressive deterioration with time was noted up to day 28, while F344-to-LEW grafts exhibited only mild injuries similar to LEW-to-LEW. In addition, flow cytometric analyses of F344-to-WKy EVLP-to-LTx revealed a sharp rise in activation marker expression in lung graft T cells beginning at day 3.

Conclusions

Our F344-to-WKy EVLP-to-LTx model generates reproducible and clinically relevant histological, radiological, and immunological results similar to those seen in humans. The model is therefore well suited to experimental EVLP studies with long-term follow-up prior to moving to large animal and human studies.