Could Hibernators Hold The Key To Improving Organ Preservation?

Studies help uncover how hibernating animals adjust their physiology to increase the tolerance of their liver and other organs to very low temperatures

April 9, 2003 (San Diego, CA) -- Each day about 63 people receive an organ transplant, but another 16 people on the waiting list die because not enough organs are available.  “Available” is the operative word in this shortage of transplantable organs. 

A donor’s gift may be available, but the transportation time to the sick patient, coupled with the period that an organ can be safely preserved without damage, may indicate that those on the waiting list are victims of logistics as well as availability.

Currently, organs such as the liver or pancreas can be stored for 36 hours, though damage occurs after a day.  Hibernating mammals may provide new insights to extend storage times and improve the quality of cold-stored organs.  Each winter, hibernators such as ground squirrels and marmots undergo periods of torpor in which body temperature and metabolic rate are only a fraction of normal levels, without damage to their organs.  For weeks at a time, hibernators maintain a body temperature close to zero degrees Celsius, which is similar to that used for human organ preservation.

Researchers at the University of Wisconsin and the University of Colorado set out to study hibernating mammals as a model for organ tolerance to extended cold preservation.  The researchers are Dr. Hannah Carey at the University of Wisconsin-Madison School of Veterinary Medicine, Dr. James Southard at the UW-Madison Medical School and Dr. Sandy Martin at the University of Colorado Health Sciences Center in Denver.  Their findings are being presented at Experimental Biology 2003, a conference sponsored by the American Physiological Society, being held April 11-15, 2003 at the San Diego Convention Center, San Diego, CA.

Background

Previous studies from this research team suggest that livers from hibernating ground squirrels show superior tolerance to extended cold storage when compared to a non-hibernator, such as the rat. The tolerance in summer squirrels is intermediate between the two. In their current study the researchers examined possible mechanisms by which a hibernating species may exhibit high tolerance to organ cold storage.

Methodology

The scientists and their colleagues compared harvested livers from torpid ground squirrels, from rats (which don’t hibernate), and from ground squirrels in summer (when they are not hibernating).  The livers were stored at 4^o C for 0-72 hours in the University of Wisconsin solution, which is the preferred solution for organ storage used world-wide.  Following cold storage the livers were perfused in vitro for 60 minutes at 37^o C.

Results

The current and earlier studies have revealed several mechanisms that may be responsible for the superior resistance of hibernator livers to cold storage:

• Greater tolerance of liver endothelial cells to withstand cold storage and warm reperfusion. Whereas many liver endothelial cells from rats die after 72 hours of cold storage, those from squirrel livers are largely unaffected by storage for this period of time. This effect likely results in better maintenance of liver microcirculation after extended cold storage, when organs are reperfused with blood after the storage period. Other preliminary evidence suggests that the proportion of the liver that is receiving flow after extended cold storage is greatly reduced in rats, but remains close to normal levels in squirrels.

• Ground squirrels have higher levels of nitric oxide synthase (NOS) in their livers when they are hibernating compared with the summer state. This increase in NOS may help to maintain the liver microcirculation after cold storage and reperfusion, because NOS activity produces the chemical messenger nitric oxide, which is a potent vasodilator.

• Specialized immune cells in the liver -- known as Kupffer cells -- are activated inappropriately in rat livers after long-term cold storage followed by warm reperfusion. Studies by other scientists have shown that this can lead to the release of potentially damaging chemicals, such as reactive oxygen species and pro-inflammatory cytokines that can produce oxidative stress. In contrast, there is little evidence of activation of Kupffer cells in hibernator livers after long-term cold storage, an effect that should reduce liver damage. Hibernator livers also maintain gluthathione redox balance to a better degree than do rats with increasing cold storage time. Because glutathione is an antioxidant, this is another mechanism by which hibernator organs may be protected from cold ischemia/reperfusion injury.

• A transcription factor, NF-kB, which can initiate pro-inflammatory pathways and has been implicated in liver injury after cold storage/reperfusion, is activated in rat livers.  This occurs after 24 hours of cold storage in rat livers, but it is not activated in livers of hibernators.

• Hibernators have much higher levels of a protective protein (known as HSP70) in their livers than do rats. HSP70 has been shown in other studies to confer protection to tissues and organs when they are stressed, such as after cold storage and reperfusion.

Conclusions

Taken together, the current and earlier studies provide exciting new directions that will help researchers identify the specific mechanisms that hibernators use to avoid tissue and organ damage during the highly altered physiology that accompanies hibernation. By fully understanding these mechanisms, these researchers believe that therapeutic advances can be developed which will protect human organs during trauma states and organ transplantation.

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The American Physiological Society (APS) is one of the world’s most prestigious organizations for physiological scientists. These researchers specialize in understanding the processes and functions underlying human health and disease.  Founded in 1887 the Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals each year.

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Editor’s Note: For receive a copy of the abstract, or to schedule an interview with a member of the research team, please contact Donna Krupa at 703.967.2751 (cell), 703.527.7357 (office) or  at djkrupa1@aol.com.