Background:High mobility group box 1 (HMGB1) was found to have both a beneficial intracellular role and injurious extracellular role after a sterile inflammatory insult.Hepatocyte-specific HMGB1 deletion even worsened the injury and the inflammation in liver ischemia-reperfusion injury (IRI). Down-regulation of nuclear HMGB1 by small interfering RNA (siRNA) may not only decrease its injurious extracellular role by reducing its release, but also make its beneficial intracellular role less affected, thus may protect against hepatic IRI. Methods:A non-lethal liver IRI model was established in mice by segmental (70%) hepatic warm ischemia for 1 hour and reperfusion for 6 hours. HMGB1-siRNA could achieve approximately 60-70% of reduction in the nuclear HMGB1 expression in livers at 48 h after the treatment. Results:The knockdown of nuclear HMGB1 expression dramatically reduced both the degree of nuclear-cytoplasmic translocation of HMGB1 during hepatic ischemia and the HMGB1 release after hepatic reperfusion, which resulted in significant preservation of liver function and a marked reduction in pathological damage, including sinusoidal congestion, hepatocellular necrosis or apoptosis, and neutrophil infiltration. Additionally, HMGB1-siRNA pretreatment markedly inhibited the increases in hepatic expression of TLR4, TLR2, RAGE, TNF-a, IL-1b, IL-6, MCP-1, iNOS, and COX-2 seen in control mice at 6 h after hepatic I/R. Conclusion:We conclude that down-reglulation of nuclear HMGB1 by siRNA reduces HMGB1 release and protects against liver IRI, highlighting the potential for siRNA-based therapy in clinical liver transplantation.

CITATION INFORMATION: Zhao G, Fu C, Wang L, Zhu L, Chen S, Chen G. Down-Regulation of Nuclear HMGB1 by Small Interfering RNA Protects Against Liver Ischemia-Reperfusion Injury. Am J Transplant. 2017;17 (suppl 3).

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