Date: Tuesday, May 2, 2017
Session Name: Concurrent Session: Pathways in Ischemia Reperfusion
Session Time: 4:30pm-6:00pm
Presentation Time: 5:42pm-5:54pm
Background: Glucocorticoid receptor (GR) serves as a receptor for relaxin (RLX), a pregnancy hormone, with novel vasoactive and tissue remodeling properties. A phase III clinical trial evaluating the efficacy, safety and tolerability of serelaxin, the recombinant form of human RLX, in acute heart failure patients is underway. Although serelaxin may exert anti-oxidative functions in murine models of cardiac, lung and renal IRI, its effects in liver transplant recipients remain unknown. Aim: To analyze as to whether and how GR – RLX signaling may affect IR-stressed orthotopic liver transplantation (OLT). Methods/Results: [Experimental arm] We evaluated hepatocellular function in mouse OLT subjected to 18h of cold storage; and in H2O2-stressed native hepatocyte cultures. Treatment with RLX increased GR expression in hepatocytes in vitro and reduced hepatocellular damage in IR-stressed OLT. These effects were GR-dependent (siRNA silencing). RLX-induced GR reduced hepatocyte HMGB1 release, accompanied by decreased TLR4/RAGE; downstream IL1β, MCP1, TNFα, CXCL10 program; and neutrophil/macrophage OLT sequestration. RLX treatment increased anti-apoptotic Bcl-2/Bcl-xL while decreasing caspase 3/caspase 8 expression. [Clinical arm] Twenty-one adult primary orthotopic liver transplant patients were recruited under IRB protocol. Liver graft biopsies (Bx; taken at 2h after reperfusion) were analyzed by Western blots, based on high (n=10) vs. low (n=11) GR levels. The high-GR Bx group showed increased Bcl-2 (p<0.05) and Bcl-xL (p<0.05), and decreased caspase 3 (p<0.05) levels as compared with low-GR group. The molecular IRI-OLT signature was correlated with the hepatocellular function (ALT, AST, total bilirubin) at POD1-POD7. Remarkably, high-GR liver transplant patient group experienced superior clinical outcomes and survival (100% vs. 63.6%, p=0.0392), with median follow-up period of 712 days (range, 27-1009 days). Conclusion: This is the first study to document that GR – relaxin signaling exerts potent cytoprotection in IRI-OLT. By antagonizing hepatocyte apoptosis and innate immune activation, serelaxin may serve as a novel treatment in liver transplant patients.
CITATION INFORMATION: Kageyama S, Nakamura K, Sossa R, Reed E, Datta N, Zarrinpar A, Busuttil R, Kupiec-Weglinski J. Glucocorticoid Receptor – Relaxin Signaling in Liver Transplant Ischemia-Reperfusion Injury (IRI): From Bench-to-Bedside. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Kageyama S, Nakamura K, Sossa R, Reed E, Datta N, Zarrinpar A, Busuttil R, Kupiec-Weglinski J. Glucocorticoid Receptor – Relaxin Signaling in Liver Transplant Ischemia-Reperfusion Injury (IRI): From Bench-to-Bedside. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/glucocorticoid-receptor-relaxin-signaling-in-liver-transplant-ischemia-reperfusion-injury-iri-from-bench-to-bedside/. Accessed February 23, 2019.
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