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Ischemia-reperfusion (IR) injury after lung transplantation is still today an important complication in up to 25% of patients. The Organ Care System (OCS) Lung, an advanced normothermic ex vivo lung perfusion system, was found to be effective in reducing primary graft dysfunction compared to standard organ care (SOC) but studies on tissue/molecular pathways that could explain these more effective clinical results are lacking. This observational longitudinal study aimed to investigate IR injury in 68 tissue specimens collected before and after reperfusion from 17 OCS and 17 SOC preserved donor lungs. Several tissue analyses including apoptosis evaluation and inducible nitric oxide synthase (iNOS) expression (by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction) were performed. Lower iNOS expression and apoptotic index were distinctive of OCS preserved tissues at pre- and post-reperfusion times, independently from potential confounding factors. Moreover, OCS recipients had lower acute cellular rejection at the first 6-month follow-up. In conclusion, IR injury, in terms of apoptosis and iNOS expression, was less frequent in OCS- than in SOC-preserved lungs, which could eventually explain a better clinical outcome. Further studies are needed to validate our data and determine the role of iNOS expression as a predictive biomarker of the complex IR injury mechanism., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)