Normothermic Ex Vivo Pancreas Perfusion and Apoptosis Modulation: A Mechanistic Appraisal

We read with interest the recent report by Parmentier et al,1 who provide a carefully designed and biologically insightful evaluation of normothermic ex vivo pancreas perfusion (NEVP) in a porcine transplantation model. The authors demonstrate that introducing a 3-h NEVP interval after static cold storage leads to measurable attenuation of reperfusion-associated apoptosis and oxidative DNA injury—injury domains that are central to the early pathophysiology of pancreas graft dysfunction. As highlighted in the recently published commentary by Gopal et al,2 these findings directly contribute to the ongoing discourse on the feasibility and mechanistic value of NEVP for pancreas preservation and help situate this protocol within current expert perspectives. A particularly compelling strength of the study lies in the alignment between terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) staining and 8-hydroxy-2-deoxyguanosine quantification.1 These markers, although distinct, converge mechanistically: TUNEL reflects DNA fragmentation associated with apoptotic cell death, whereas 8-hydroxy-2-deoxyguanosine serves as a sensitive indicator of oxidative mitochondrial stress.3 The observed parallel reduction in both endpoints after NEVP suggests a coordinated dampening of oxidative injury and downstream apoptotic signaling. This pattern is consistent with established mechanistic data from myocardial and hepatic ischemia/reperfusion settings, where modulation of oxidative burden has been shown to alter apoptotic propagation.3 The coherence between these injury readouts strengthens the biological plausibility of the authors’ findings. However, several technical considerations warrant further reflection. First, although TUNEL staining is widely used, it does not exclusively discriminate between apoptotic and necrosis-associated DNA fragmentation, particularly during early reperfusion when mixed cell death pathways may overlap.4 Second, although NEVP reduced oxidative stress on postoperative day 3, the absence of early reperfusion sampling limits conclusions regarding the initial oxidative surge. Importantly, within the broader landscape of normothermic machine perfusion, this NEVP protocol offers specific advantages for pancreas transplantation because the pancreas uniquely requires low perfusion pressures and tightly regulated microvascular flow; the controlled 3-h normothermic interval used by Parmentier et al1 provides physiologic perfusion without exceeding these thresholds, thereby mitigating edema, hemorrhage, and microcirculatory injury that have historically limited normothermic machine perfusion application in pancreas grafts. From a methodological standpoint, the authors provide valuable evidence supporting the feasibility and stability of NEVP; however, key metabolic indicators that have become standard in liver and kidney perfusion—such as ATP recovery, lactate clearance, or functional acinar parameters—were not assessed.5 Their inclusion would have strengthened the translational relevance of NEVP as a viability assessment tool. In addition, the selected 3-h perfusion interval, atlhough reasonable, may be insufficient to capture the slower metabolic recovery typical of pancreatic tissue, raising the possibility that extended perfusion could yield further insights into functional restoration. Despite these limitations, the study by Parmentier et al represents a meaningful mechanistic advance. Their findings reinforce the concept that NEVP can interrupt early injury pathways, particularly those related to oxidative stress and apoptosis, and provide a foundation for future work aimed at refining perfusion protocols, extending perfusion duration, and integrating metabolic or mitochondrial markers to improve the predictive value of preimplantation pancreas assessment.