Article

Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.74). 04/2005; 288(3):G473-80. DOI: 10.1152/ajpgi.00223.2004
Source: PubMed

ABSTRACT The success of liver grafts is currently limited by the length of time organs are cold preserved before transplant. Novel insights to improve viability of cold-stored organs may emerge from studies with animals that naturally experience low body temperatures (T(b)) for extended periods. In this study, we tested whether livers from hibernating ground squirrels tolerate cold ischemia-warm reperfusion (cold I/R) for longer times and with better quality than livers from rats or summer squirrels. Hibernators were used when torpid (T(b) < 10 degrees C) or aroused (T(b) = 37 degrees C). Livers were stored at 4 degrees C in University of Wisconsin solution for 0-72 h and then reperfused with 37 degrees C buffer in vitro. Lactate dehydrogenase (LDH) release after 60 min was increased 37-fold in rat livers after 72 h cold I/R but only 10-fold in summer livers and approximately three- to sixfold in torpid and aroused hibernator livers, despite twofold higher total LDH content in livers from hibernators compared with rats or summer squirrels. Reperfusion for up to 240 min had the least effect on LDH release in livers from hibernators and the greatest effect in rats. Compared with rats or summer squirrels, livers from hibernators after 72 h cold I/R showed better maintenance of mitochondrial respiration, bile production, and sinusoidal lining cell viability, as well as lower vascular resistance and Kupffer cell phagocytosis. These results demonstrate that the hibernation phenotype in ground squirrels confers superior resistance to liver cold I/R injury compared with rats and summer squirrels. Because hibernation-induced protection is not dependent on animals being in the torpid state, the mechanisms responsible for this effect may provide new strategies for liver preservation in humans.

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    • "It seems reasonable to suggest that moesin expression is an adaptation to hypothermia, which is consistent with our observations of the moesin defect in cold stored livers from non-hibernating mammals. In fact, livers retrieved from actively hibernating ground squirrels were determined to be resistant to cold storage injury, relative to cold stored livers retrieved from either non-hibernating summer active ground squirrels or from other non-hibernating rodent species like rats [14]. It is not known from these studies whether hibernating ground squirrels also have higher expression levels of moesin in the liver, like they do in their intestine, or if they express a more heavily phosphorylated moesin protein in the liver that would provide for more structural functionality. "
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    • "Resistance to cerebral ischemia/reperfusion injury in the arctic ground squirrel does not require preparation for the hibernation season or the hibernation state Resistance to brain injury following cardiac arrest in summer active (euthermic) AGSs led to doubt about how much of the tolerance to I/R noted in AGSs was due to the hibernation season and how much was intrinsic to the species. Liver and intestine isolated from the thirteen-lined ground squirrel during inter-bout arousal resist I/R injury; however, tolerance is lost or decreased when tissue is obtained from animals during the summer season (Kurtz et al., 2006; Lindell et al., 2005 "
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    • "Upon arousal, despite the potential for reperfusion injury during torpor/arousal cycles, hibernators do not show signs of massive cell death (Zancanaro et al., 1999; Fleck and Carey, 2005; van Breukelen et al., 2010). Experimental cold ischemia/reperfusion of livers derived from torpid, aroused, and summer 13-lined ground squirrels and laboratory rats revealed that the hibernation phenotype is associated with an increased resistance to cold ischemia/ reperfusion-injury, suggested by a better preserved mitochondrial respiration, bile production, and sinusoidal lining cell viability, lower vascular resistance and Kupffer cell activation ex vivo (Lindell et al., 2005). The increased resistance to ischemia/reperfusion induced injury (I/R-injury) was later confirmed in vivo, by showing decreased mucosal damage in hibernators following intestinal warm ischemia/reperfusion (Kurtz et al., 2006). "
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