Inhibition of High Mobility Group Box 1-Toll-Like Receptor-4 Signaling by Glycyrrhizin Contributes to the Attenuation of Cold Ischemic Injury of Liver in a Rat Model

Abstract

Background: Cold ischemic injury in liver storage is an important issue pertaining to liver transplantation. Glycyrrhizin (GL), the glycoconjugated triterpene produced by the root of the licorice plant, has been used to treat chronic hepatitis; however, its function against cold ischemia injury remains unknown.

Methods: Livers from Wistar rats were reperfused at 37°C for 60 minutes either immediately or after 24 hours of cold storage in histidine-tryptophan-ketoglutarate (HTK) solution containing different concentrations of GL (n = 30 for each group). Bile and lactate dehydrogenase (LDH) levels in the effluent perfusates were determined. Apoptotic cells, high mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), and nuclear factor (NF)-κB in liver grafts were assessed. The levels of inflammatory mediators (tumor necrosis factor [TNF]-α, interleukin [IL]-6) in the effluent perfusates were measured.

Results: Addition of GL to HTK solution significantly attenuated ischemic injury during reperfusion in a dose-dependent way, as evidenced by the lower liver injury scores, lower LDH leakage, and increased bile secretion. After reperfusion, livers stored in HTK solution containing GL had decreased expression of HMGB1, TLR4, and NF-κB, and less apoptosis compared with those stored without GL. The levels of TNF-α and IL-6 in the effluent were also decreased when stored in GL-containing HTK solution.

Conclusion: The addition of GL to HTK solution attenuates cold ischemic injury during cold storage and the mechanism is at least partially attributable to the inhibition of TLR4 signaling.