The role of NPY in liver transplantation from extended-criteria donors

Donor shortage has increased liver transplantation (LT) waiting lists. The use of livers grafts from extended criteria donors (ECD), including deceased donors with alcoholic liver disease (ALD) or severe steatosis, particularly after prolonged cold ischemia (CI), is associated with a risk of graft dysfunction and reduced post-liver transplantation outcomes. This study investigated whether hepatic NPY depletion in donors after brain death (DBD) and donors after cardiocirculatory death (DCD) contributes to liver injury and regenerative failure. Rat models of donors after brain death (DBDs) or cardiocirculatory death (DCDs) with ALD or severe steatosis were used to assess how hepatic sympathetic nervous system (SNS) modulation, adrenal medulla (AM) removal, NPY (alone or with norepinephrine, NE), and AMPK-NO signalling affect liver damage and regeneration before retrieval from donors and after 24 h CI followed by ex vivo reperfusion or transplantation. In DBDs, SNS-derived hepatic NPY decreased, while NE was preserved thanks to AM. In DCDs, both NPY and NE (derived from SNS) were depleted. NPY administration (but not SNS stimulation) restored hepatic NPY and protected DBD grafts against damage and regenerative failure. In DCDs, only combined NPY + NE or SNS stimulation restored both NPY and NE, reducing damage but not improving regeneration. Protection in both donor types depended on AMPK-NO signalling, which was reduced before retrieval and restored by NPY (DBDs), NPY + NE or SNS stimulation (DCDs). Protection depended on AMPK-NO signaling and persisted after CI and reperfusion, improving survival. In contrast, AMPK activator, AICAR-which increased NO- and NO supplementation caused excessive NO after CI and reperfusion, increasing peroxynitrite generation, oxidative stress, liver damage and regenerative failure. The donor-type-specific drugs/interventions (NPY in DCDs; NPY + NE or ES stimulation in DCDs) might improve clinical LT outcomes from extended-criteria donors, whereas AICAR or NO supplementation is detrimental.