NRF2 in liver injury and repair: its relevance to liver transplantation
Citation:
Ahmed, Ola, NRF2 in liver injury and repair: its relevance to liver transplantation, Trinity College Dublin, School of Medicine, Clinical Medicine, 2022Download Item:
Abstract:
Liver transplantation is the only effective curative treatment for end-stage liver disease and modern-day practice has led to excellent survival outcomes. Ensuring access to suitable allografts remains crucial as patients who are unable to receive an organ face a dismal prognosis on the wait list. This challenge has been further complicated by dynamic changes to population health owing to the rise in metabolic conditions which have impacted the quality of the current donor pool and utility of potential allografts. Interventions to increase the donor pool have recently focused on increasing the use of extended criteria or marginal allografts that would otherwise be rejected while also reducing organ discard. The challenge in using marginal livers is in their inability to withstand ischaemia reperfusion injuries and regenerate after the post-operative period. Given the critical role of inflammatory and antioxidant pathways during the reperfusion process, defining the molecular mechanisms of allograft injury and marginal liver responses during this period may help identify therapeutic targets and salvage a proportion of discarded organs.
Upon reperfusion, a burst of reactive oxygen species (ROS) leads to the activation of several physiological processes involved in both tissue injury and repair. During this process, ROS further stimulate the NRF2 mediated pathway which has antioxidant, anti-inflammatory and regenerative functions. The pathway plays a key role in cellular defence and may have critical effects on liver allograft stress. The overall aim of this thesis was to assess the relevance of this axis in discarded and marginal liver allografts with a view to targeting the pathway, especially in fatty livers, to improve functionality.
NRF2 protein was measured in discarded human liver allografts and variable levels were observed. Increased expression of NRF2 was linked to favourable hepatic clinical parameters and less evidence of inflammatory injury. NRF2 levels could therefore become a useful indicator of marginal allograft selection in the clinical setting. Using an ex vivo normothermic machine preservation model, livers were exposed to six hours of perfusion and hepatic viability was investigated. Livers with higher levels of NRF2 consistently demonstrated superior functional profiles compared to livers with lower or absent NRF2 levels.
Steatotic livers demonstrated significantly lower NRF2 levels when compared to lean livers suggesting their increased susceptibility to injury during surgery. Interestingly, the results indicate that steatosis does not automatically imply marginality. To explore this further, experiments were performed to identify a relative cut-off value for steatosis in which NRF2 may still function. Some, moderately steatotic and, on occasion, severely steatotic livers maintained intact NRF2 axes, emphasizing the potential of hepatic NRF2 activity as an important predictive marker of organ suitability.
Following on from the previous findings, NRF2 was then modulated in a fatty liver rodent model using a pharmacologic agent (Oltipraz) in combination with the benefits of ex vivo preservation. The results suggest that an NRF2 agonist can be used effectively to increase activity at a nuclear level allowing steatotic livers to resist significant reperfusion injury.
Evolving population demographics and the resurgence of metabolic syndromes have unequivocally impacted access to suitable allografts. Identifying which livers can be salvaged for clinical use may help bridge the gap between the donor and recipient pool. Encouragingly, the NRF2 pathway can offer insight into the inflammatory responses and regenerative potential of livers during the transplantation process. The findings from this work can help improve our current understanding of allograft injury and propose additional systems for all organ development and selection.
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APPROVED
Author: Ahmed, Ola
Advisor:
O'Farrelly, ClionaPublisher:
Trinity College Dublin. School of Medicine. Discipline of Clinical MedicineType of material:
ThesisCollections
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