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

Abstract

. Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype. Am J Physiol Gastrointest Liver Physiol 288: G473-G480, 2005; doi:10.1152/ajpgi.00223.2004.-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 Ͻ 10°C) or aroused (Tb ϭ 37°C). Livers were stored at 4°C in University of Wisconsin solution for 0 -72 h and then reperfused with 37°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. transplantation; cold storage; Kupffer cells; sinusoidal lining cells DESPITE MAJOR ADVANCES IN hypothermic preservation of organs before transplant, problems associated with extended cold ischemia-reperfusion (cold I/R) injury still limit the optimal use of transplantation as a therapeutic intervention for organ failure. For example, human livers can be successfully stored at 4°C for up to 12 h in University of Wisconsin (UW) solution, but graft failure is greatly increased after extended storage periods (14,33,34). In the rat liver transplant model, when livers are cold stored in UW for up to 24 h, 100% of the recipients survive (42); in contrast, without nutritional manipulation, none survive after receiving livers stored for 48 h (39).The damaging effects of cold I/R are evident on organ reperfusion with warmed, oxygenated blood, with damage increasing with the length of the cold ischemia period (10,35,40).A variety of pharmacological strategies has been explored to improve graft function after cold I/R to extend cold storage times and provide more flexibility in organ distribut...

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

“…This constitutes a significant metabolic stress, and it has been suggested that hibernators either constitutively express higher levels of antioxidant enzymes than non-hibernating species or that hibernators upregulate antioxidant enzymes to protect against oxidative damage. Indeed, hibernators have been reported to avoid oxidative stress associated with arousal (Ma et al 2005) and, similar to dwarf mice, show evidence of cellular stress resistance (Lindell et al 2005;Kurtz et al 2006;Dave et al 2006). We previously showed that 13-lined ground squirrels do not upregulate intracellular antioxidant enzyme activities in brain, heart or liver tissue during hibernation (Page et al 2009a).…”

Persistent Tolerance to Oxygen and Nutrient Deprivation and N-methyl-D-Aspartate in Cultured Hippocampal Slices from Hibernating Arctic Ground Squirrel

“…Euthermic AGS are able to tolerate global ischemia, induced via cardiac arrest, without loss of CA1 neurons (Dave et al, 2005). Additionally, organs from TLS, whether in the euthermic or torpid state, tolerate cold ischemia-reperfusion injury (Lindell et al, 2005). Furthermore, acute hippocampal slices from euthermic TLS tended to tolerate OGD better than slices from rat at 361C; however, this tendency was not statistically significant (Frerichs and Hallenbeck, 1998).…”

Arctic Ground Squirrel (Spermophilus Parryii) Hippocampal Neurons Tolerate Prolonged Oxygen—Glucose Deprivation and Maintain Baseline ERK1/2 and JNK Activation Despite Drastic ATP Loss

“…Recent, repeated bouts of torpor were not necessary for OGD tolerance in summer euthermic AGS, suggesting that low body temperatures experienced during torpor do not augment OGD tolerance through hypoxic preconditioning. In other tissues, a seasonal effect of resistance to ischemic damage has been shown where summer animals show increased vulnerability to insult (Kurtz et al, 2006;Lindell et al, 2005). Further analysis of AGS sampled earlier in the summer season will be necessary to determine if seasonal factors associated with preparation for hibernation promote tolerance to OGD.…”