To address the shortage of organs for transplantation many use “marginal” livers, which are particularly susceptible to ischemia-reperfusion injury (IRI). We have taken a two-pronged approach to address this issue. In the “murine” arm, we discovered that Nrf2 deficiency in the donor liver, a master regulator of intracellular redox homeostasis, exacerbated IRI in mouse orthotopic liver transplantation (BL6→BL6; 20h of cold storage). However, IRI was mitigated if donor livers were pre-conditioned with bone marrow cells overexpressing anti-oxidant HO-1. The success of donor liver “rejuvenation” was lost after abrogation of SIRT1 activity, a NAD+-dependent type III protein deacetylase with key stress resistance functions. Thus, SIRT1 signaling dictates the rejuvenation outcomes in mouse livers, in which Nrf2 expression represents a denominator of donor tissue quality. In the ongoing “clinical” arm, we enrolled 53 liver transplant patients in which portal blood and liver perfusate are collected pre-op; during; and at reperfusion. The severity of liver damage is assessed by a new biopsy pathology scoring system, i.e., minimal/mild IRI (score 1-2) vs. moderate/severe IRI (score 3-4), based on incidence of cholestasis, inflammation, steatosis, ballooning/necrosis.

Fig. 1A shows a human liver transplant transcriptome (mRNA pool), as indicated by the heat-map at the bottom. The first column is of the average gene expression in pre-transplant biopsies (n=10). The first sample grouped column (#1-4) represents moderate/severe IRI; the next column (#5-10) identifies minimal/mild IRI. The Gene Ontology analysis (Fig. 1B) associates the severe IRI cases with higher expression of genes with function in the immune system, defense/stress responses, and metabolic processes. Strikingly, and in agreement with our murine OLT/IRI functional data, human livers suffering from severe IRI showed ca. 2.5-fold lower induction of Nrf2, HO-1 and SIRT1 genes, compared to IRI-resistant grafts. These findings provide rationale for innovative donor interventions to improve the quality and size of the current liver organ supply.

CITATION INFORMATION: Zarrinpar A, Ke B, Ji H, Reed E, Busuttil R, Kupiec-Weglinski J. Liver Graft Rejuvenation Prior to Transplantation: A Bench-to-Bedside Approach. Am J Transplant. 2016;16 (suppl 3).

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