NRF2 assessment in discarded liver allografts: A role in allograft function and salvage
| Autor: | Cliona O'Farrelly, Brian W. Wong, Min Xu, Ola Ahmed, Yiing Lin, Alexander N Wein, Fangyu Zhou, William C. Chapman, Gundumi A. Upadhya, Li Ye |
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| Rok vydání: | 2022 |
| Předmět: |
Agonist
NF-E2-Related Factor 2 medicine.drug_class CD3 Pharmacology medicine.disease_cause digestive system environment and public health Transaminase Parenchyma Animals Immunology and Allergy Medicine Pharmacology (medical) Transplantation Machine perfusion biology business.industry Organ Preservation respiratory system Allografts Liver Transplantation Rats Perfusion Liver Reperfusion Injury biology.protein Biomarker (medicine) Liver function business Oxidative stress |
| Zdroj: | American Journal of Transplantation. 22:58-70 |
| ISSN: | 1600-6135 |
| DOI: | 10.1111/ajt.16789 |
| Popis: | Antioxidant defence mechanisms, such as the nuclear factor-erythroid 2-related-factor-2 (NRF2) axis, are integral to oxidative stress responses and ischemic injury. Hepatic antioxidant capacity is contingent on parenchymal quality, and there is a need to develop new insights into key molecular mechanisms in marginal liver allografts that might provide therapeutic targets. This study examines the clinical relevance of NRF2 in donor livers and its response to normothermic machine perfusion (NMP). Discarded donor livers (n = 40) were stratified into a high NRF2 and low NRF2 group by quantifying NRF2 expression. High NRF2 livers had significantly lower transaminase levels, hepatic vascular inflammation and peri-portal CD3+ T cell infiltration. Human liver allografts (n = 8) were then exposed to 6-h of NMP and high NRF2 livers had significantly reduced liver enzyme alterations and improved lactate clearance. To investigate these findings further, we used a rat fatty-liver model, treating livers with an NRF2 agonist during NMP. Treated livers had increased NRF2 expression and reduced transaminase derangements following NMP compared to vehicle control. These results support the association of elevated NRF2 expression with improved liver function. Targeting this axis could have a rationale in future studies and NRF2 agonists may represent a supplemental treatment strategy for rescuing marginal donor livers. |
| Databáze: | OpenAIRE |
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