Hepatic ischemia-reperfusion injury (IRI) represents a major risk factor of early graft dysfunction and acute/chronic rejection as well as a key obstacle to expanding the donor pool in orthotopic liver transplantation (OLT). Although glucocorticoid receptor (GR) signaling may enhance graft cytoprotective programs, clinical use of glucocorticoid is limited due to its adverse effects, while clinical relevance of GR-facilitated cytoprotection in OLT recipients remains unknown. We aimed to evaluate the significance of hepatic GR in clinical OLT and verify the impact of recombinant human relaxin (rhRLX), which may function as a GR agonist in tissue/disease-specific manner. Fifty-one liver transplant patients were recruited under IRB protocol. Liver biopsies were collected after cold storage (prior to put-in) and 2h post-reperfusion (prior to abdominal closure), followed by Western blot-assisted analyses. Forty-three percent of OLTs failed to increase GR peri-operatively under the surgical stress. Post-/pre-GR ratios ([Delta]GR) at POD1 correlated negatively with serum AST (r=-0.3144, p=0.0247) / cleaved caspase-3 (r=-0.3394, p=0.0148) and positively with Bcl-xL (r=0.4349, p=0.0014) / Bcl-2 (r=0.3354, p=0.0161) levels. Recipients with [Delta]GR >1.1 (n=25) showed lower incidence of early allograft dysfunction (0.0% vs 11.5%) and superior post-OLT survival (2-year: 92.5% vs 80.8%) as compared to those with [Delta]GR <1.1 (n=26). In a murine OLT model with extended (18h) cold storage, treatment with rhRLX ameliorated IR-damage and improved survival while upregulating hepatocyte GR and Bcl-xL/Bcl-2 expression in OLT. rhRLX-induced GR suppressed hepatocyte HMGB1 translocation/release, accompanied by decreased TLR4/RAGE, suppressed IL1β, CCL2, CXCL10, TNFα, CXCL1, CXCL2 levels, and attenuated neutrophil/macrophage accumulation in OLT. Inhibition of GR in hepatocyte cultures and in OLT diminished rhRLX-mediated cytoprotection. Conclusion: This translational study underscores the role of rhRLX – GR signaling as a novel regulator of hepatocellular protection against IR-stress in liver transplantation. In the context of a recent phase III clinical trial demonstrating positive and safe outcomes of rhRLX in acute heart failure patients, studies on rhRLX for the management of OLT recipients are warranted.

CITATION INFORMATION: Kageyama S., Nakamura K., Ito T., Aziz A., Ke B., Sossa R., Reed E., Kaldas F., Busuttil R., Kupiec-Weglinski J. Recombinant Relaxin Protects Liver Transplants from Ischemia-Reperfusion Damage via Hepatocyte Glucocorticoid Receptor: From Bench-to-Bedside Am J Transplant. 2017;17 (suppl 3).

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