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Hibernation reduces cellular damage caused by warm hepatic ischemia–reperfusion in ground squirrels

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Abstract

During the hibernation season, livers from 13-lined ground squirrels (Ictidomys tridecemlineatus) are resistant to damage induced by ex vivo, cold ischemia-warm reperfusion (IR) compared with livers from summer squirrels or rats. Here, we tested the hypothesis that hibernation also reduces damage to ground squirrel livers in an in vivo, warm IR model, which more closely resembles complications associated with traumatic injury or surgical interventions. We also examined whether protection is mediated by two metabolites, inosine and biliverdin, that are elevated in ground squirrel liver during interbout arousals. Active squirrels in spring and hibernators during natural arousals to euthermia (body temperature 37 °C) were subject to liver IR or sham treatments. A subset of hibernating squirrels was pre-treated with compounds that inhibit inosine synthesis/signaling or biliverdin production. This model of liver IR successfully induced hepatocellular damage as indicated by increased plasma liver enzymes (ALT, AST) and hepatocyte apoptosis index compared to sham in both seasons, with greater elevations in spring squirrels. In addition, liver congestion increased after IR to a similar degree in spring and hibernating groups. Microvesicular steatosis was not affected by IR within the same season but was greater in sham squirrels in both seasons. Plasma IL-6 increased ~twofold in hibernators pre-treated with a biliverdin synthesis inhibitor (SnPP) prior to IR, but was not altered by IR in untreated squirrels. The results show that hibernation provides protection to ground squirrel livers subject to warm IR. Further research is needed to clarify mechanisms responsible for endogenous protection of liver tissue under ischemic stress.

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Acknowledgements

We thank Dr. Jonathan McAnulty for assistance with development of the IR model, Michael Grahn for assistance with animal care, Nathan Nelson for technical advice, Dr. Cecile Áne for statistical consultation, and Dr. Hjalmar Bouma for constructive criticism of the manuscript. A.P. was supported during this work by NIH T32 017503.

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Correspondence to Hannah V. Carey.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the Univeristy of Wisconsin-Madison, where the studies were conducted.

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Communicated by G. Heldmaier.

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Otis, J.P., Pike, A.C., Torrealba, J.R. et al. Hibernation reduces cellular damage caused by warm hepatic ischemia–reperfusion in ground squirrels. J Comp Physiol B 187, 639–648 (2017). https://doi.org/10.1007/s00360-017-1056-y

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