Ischemia-reperfusion injury (IRI) is a consequence of liver resection and liver transplantation. The Nrf2-antioxidant response element pathway is a key mediator of cellular defense against oxidative stress. We have shown that transgenic mice with myeloid cell-specific, over-activation of Nrf2 (LyzMcre+/caNrf2+) sustain decreased hepatocellular damage when compared to control mice (+/-) after hepatic IRI. Our study objective was to delineate the Nrf2-dependent mechanisms involved in Nrf2-induced, myeloid cell-mediated protection of hepatocytes during IRI.

LyzMcre+/caNrf2+ (+/+) and control (+/-) mice underwent 60 min of hepatic ischemia followed by 6 h of reperfusion. Serum ALT was measured using an IDEXX VetTest Analyzer. Western blot of liver tissue was performed to examine signaling proteins. Serum IL-6 levels were measured with a Luminex bead-based assay. One-way ANOVA followed by Fisher LSD post-hoc was performed. P<0.05: *(+/+) Sham vs. (+/+) IR; #(+/+) IR vs. (+/-) IR.

Serum ALT levels were lower in (+/+) mice compared to controls (648.75 ± 106.11 vs. 3214.71 ± 995.18, p=0.015). After IRI, the ratio of p-Stat3:total Stat3 signaling in hepatocytes was significantly greater in (+/+) mice compared to controls . Serum IL-6 levels were greater in (+/+) vs. controls (77.20 ± 31.56 vs. 27.39 ± 1.80, p=0.040) after IRI.

These data suggest that the combination of Nrf2 over-activation in myeloid cells and hepatic IRI may protect hepatocytes from damage through IL-6/Stat3 signaling mechanisms. Additional studies are necessary to define the mechanisms involved in transcellular cross-talk between Nrf2 induction in myeloid cells and hepatocytes during IRI.

CITATION INFORMATION: Harberg C, Lee L.-Y, Werner S, Johnson D, Johnson J, Foley D. Protective Effects of Nrf2 Over-Activation in Myeloid Cells During Hepatic Ischemia Reperfusion Correlates with Stat3 Signaling in Hepatocytes. Am J Transplant. 2016;16 (suppl 3).

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