S. J. Concors1,3, D. R. Murken1, D. D. Aufhauser1, Z. Wang1, G. Ge1, W. W. Hancock2,4, M. H. Levine1,3 1Hospital Of The University Of Pennsylvania,Surgery,Philadelphia, PA, USA 2Hospital Of The University Of Pennsylvania,Pathology And Laboratory Medicine,Philadelphia, PA, USA 3Children’s Hospital Of Philadelphia,Surgery,Philadelphia, PA, USA 4Children’s Hospital Of Philadelphia,Pathology And Laboratory Medicine,Philadelphia, PA, USA
Introduction: Hepatic ischemia/reperfusion injury (IRI) complicates liver transplantation and other surgical scenarios and can lead to early allograft dysfunction and liver failure. A better understanding of the molecular mechanisms of IRI may facilitate development of strategies to prevent and treat IRI. We have previously reported female mice tolerate renal IRI with profound reduction in injury compared to male mice and have demonstrated that supplemental estrogen mitigates renal IRI in female mice. We wished to investigate whether estrogen may provide similar protection in liver IRI.
Methods: 8-12 week old C57BL/6 iM (intact male) and iF (intact female) mice were subjected to 70% liver ischemia for 60 minutes under strict temperature control with assessment of plasma AST/ALT levels at 24 h post-IRI. Male (nM) and female (nF) mice were neutered at 3 wks of age and then subjected to liver IRI at age 8-12 wks. iM, iF, nM, and nF mice were treated with supplemental estradiol (+E2) 16 hours and 1 hour before IRI. Estrogen receptor alpha knock out (ESRaKO) female mice were also subjected to this liver IRI model.
Results: iF mice displayed a trend towards reduced liver injury after liver IRI compared to iM mice (Fig 1A). nM and nF mice displayed increased liver injury compared to iM and iF mice, respectively (Fig 1B). Supplemental estradiol administration mitigated liver IRI in both genders (Fig 1C). ESRaKO mice exhibited significantly worse transaminase levels and decreased survival after IRI (Fig 1D).
Conclusion: Neutering mice of either sex leads to impaired tolerance of liver IRI. Supplemental estradiol has a protective effect on liver IRI in both hormonally intact and neutered M, as well as females. These findings are distinct from patterns observed in setting of renal IRI, suggesting tissue-specific injury pathways. This has implications for therapeutic intervention as a wide range of hormonal therapies with either estrogen or testosterone, or both, may be useful in the treatment of liver IRI.
