Pretreatment increases liver transplant survival in rats

Pretreating transplanted livers with the immune molecule interleukin-6 (IL-6) dramatically increased survival of rats receiving organs with fatty degeneration–a common condition in humans that typically reduces transplant viability. The results suggest a means of making it possible to use a higher percentage of available donor livers for transplantation in humans. With over three times as many Americans needing transplants as there are available donor livers, an effective approach to increasing the number of viable donor organs would help narrow the gap between demand and supply.

Steatosis, or fatty liver degeneration, is present in between 13 and 50 percent of donor livers. Fat may accumulate in the liver in association with obesity, diseases such as diabetes mellitus, and heavy drinking. Donor livers with steatosis are more likely to function poorly or fail after transplantation. With the increase in obesity in this country, the prevalence of steatosis in donor livers is expected to increase. A multi-center team of scientists found that adding the cytokine or cell-signaling molecule interleukin-6 (IL-6) to the solution in which a donor liver is stored before transplantation significantly increases post-transplant survival of rats receiving organs with fatty degeneration. Bin Gao, M.D., Ph.D., at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), led the scientific team which included investigators at The Johns Hopkins University School of Medicine, Baltimore, MD (supported in part by a research grant from NIH’s National Institute on Diabetes and Digestive and Kidney Diseases) and the University of Science and Technology of China, Hefei, China.

NIAAA Director Ting-Kai Li, M.D. said, “This study is an example of how our knowledge at a molecular level of how the immune system functions to protect against tissue damage can be exploited to develop strategies for dealing with important clinical problems. The work gives us a clue for future treatment and enhances our understanding of the mechanisms of liver damage, and the protection afforded by IL-6, after transplantation.”

IL-6, one of the immune system’s complex network of signaling molecules, is known to protect against liver injury in a variety of conditions. In this study, scientists took either healthy livers from lean rats or steatotic livers (livers with fatty degeneration) from genetically obese rats and transplanted them into lean recipient rats. All of the recipients of livers from the lean rats survived (10 of 10). Thirty percent (3 of 10) of the recipients of the steatotic livers stored in standard solution survived. The addition of IL-6 to the preservative solution increased the survival rate of rats receiving steatotic livers to 91.7 percent (11 out of 12). Results were similar whether the organs were stored in the standard preservative used in transplantation (University of Wisconsin or UW solution) or normal saline solution, suggesting that the effect of IL-6 was direct and not the result of interactions with components in the UW solution.

The team compared the post-transplant condition of the organs by microscopic tissue examination (histology) and by measuring levels of liver enzymes that reflect liver function. Steatotic, but not lean, transplanted livers showed massive cell death (necrosis). Steatotic livers preserved in solution with IL-6, however, showed no significant necrosis. Results from liver enzyme tests revealed similar differences: Enzyme levels with IL-6-treated steatotic livers were closer to levels seen in the lean livers and significantly lower than those seen in untreated fatty livers.

The investigators also looked at the mechanisms of tissue damage. Previous research has suggested that after blood circulation is restored to a transplanted liver, loss of cells lining the sinuses of steatotic livers is a key first step in the subsequent damage. Fine capillary blood circulation (microcirculation) is impaired. In both cases, IL-6 protected against these destructive changes.

Cytokines like IL-6 act by setting off a cascade of other signaling molecules. A key effect of IL-6 in particular is activation of a cell survival signal molecule, STAT3. Results from this study confirmed that IL-6 increased and prolonged STAT3 activation. In practical terms, the authors point out, adding IL-6 to a preservative solution before transplantation is likely to require less IL-6 and less likely to cause side effects than giving IL-6 to transplant recipients.

According to the paper, in late 2002, 17,329 American patients were on the United Network for Organ Sharing waiting list for liver transplantation. At the same time, only 5,181 donor organs were available. The increasing rate of obesity in this country could increase, rather than decrease, the shortfall in viable organs.

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The article by Sun, Z., Klein, A.S., Radaeva, S., Hong, F., El-Assal, O., Pan, H.-N., Jaruga, B., Batkai, S., Hoshino, S., Tian, Z., Kunos, G., Diehl, A. M., and Gao, B. appears in Gastroenterology, Volume 125, pages 202-215, 2003.

For an interview with Dr. Gao, please telephone the NIAAA Press Office.

The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to science, practitioner, policy making, and general audiences.