Immune-Mechanistic Insights into Improved Lung Preservation using the Organ Care System in a Porcine Transplantation Model in Comparison to the INSPIRE Trial

Abstract

Background Portable ex vivo lung perfusion (EVLP) is a promising alternative to cold static storage for graft preservation in lung transplantation. In the clinical INSPIRE trial, lung preservation with the organ care system (OCS) resulted in reduced rates of early severe primary graft dysfunction. Here, we investigate the mechanism of improved preservation in the OCS and immunological changes in a porcine lung transplant model in order to compare the immunological changes with the findings of the INSPIRE tiral . Methods A total of 12 porcine donor lungs were retrieved after standard cold flush with LPD solution. Six lungs were preserved at normothermia in the OCS for 6 hours (OCS group) and another six lungs were preserved on ice for 6 h (standard of care, SOC group) and left lungs were transplanted into allogeneic porcine recipients. Six additional animals received sham surgery. All pigs were observed for another 6 hours after clamping the contralateral lung or sham surgery. In addition to hemodynamic and respiratory parameters, we investigated cytokines in recipient plasma and bronchoalveolar lavage (BAL) fluid and perfusates. Results In the SOC group, two animals died upon clamping of the contralateral lung due to right heart failure. All pigs in the sham group and in the OCS group survived the observation period of 6 hours. Oxygenation (PaO2/FiO2) at the end of the postoperative observation period was significantly better in the OCS group as opposed to the SOC or sham groups (PaO2/FiO2 after 6 hrs: 231.8±21.3 vs. 129.5±41.1 vs. 154.6±30.8; p<0.05). Lung compliances and pulmonary vascular resistance was higher in the OCS group compared with the SOC and sham groups. In BAL of OCS recipients at 6 h, significantly lower levels of IL-6 (p=0.04), IL-1a (p=0.04), IL-1RA (p=0.03), IL-12 (p=0.03), IL-18 (p=0.03) and IFN-g (p=0.04) were observed compared to SOC recipients. The lower plasma levels (IL-6, IL-1a, IL-18) of the OCS groups at 0.5, 2, 6h did not reach significance. In perfusates of OCS lungs, significantly higher cytokine levels were detected compared to perfusated of SOC lungs, especially the antagonist IL-1RA. Conclusion In an acute porcine lung transplantation model, arterial oxygenation was improved in recipients of lungs preserved in normothermia in the OCS compared to recipients of lungs stored on ice. Moreover, the inflammatory response in BAL and blood was significantly reduced and antagonists like IL-1RA were elevated, confirming previous findings in INSPIRE trial patients.