Researchers find “protective switches” that may make damaged livers suitable for transplantation

(Press-News.org) In a mouse model of liver transplantation, UCLA researchers have identified proteins that act as “protective switches” guarding the liver against damage occurring when blood supply is restored during transplantation, a process known as ischemia-reperfusion injury.

The finding could increase the supply of donor organs by using molecular therapies to strengthen the liver’s protective pathways. By boosting this protection,  organs that would otherwise be discarded as damaged or suboptimal could be made suitable for transplantation and added to the donor pool, said Kenneth J. Dery, Ph.D, an associate adjunct professor of surgery in the division of liver and pancreas transplantation at the David Geffen School of Medicine at UCLA and the study’s co-senior author.

“One of the most intractable problems in the field of organ transplantation remains the nationwide shortage of donor livers, which has led to high patient mortality while waiting for a liver transplant,” Dery said. “This could ultimately help address the national transplant shortage and lower mortality rates.”

The findings will be published September 23 in the peer-reviewed JCI Insight.

Hepatic ischemia-reperfusion injury (IRI) occurs when a liver’s blood supply is cut off, then restored, during transplantation. This sudden change sparks inflammation that damages the organ.

In previous research, the researchers described the role that a protein called CEACAM1 plays in protecting the liver from injury during the transplantation process. In this newest study, they discovered that CEACAM1 and another protein called Human Antigen R (HuR) together act as protective switches that prevent this damage. Using RNA tools, the researchers found that they could boost these switches, increasing their protective effect and reducing the damaging stress on the liver.

Although the researchers found this effect in mice, they also found the same protective relationship between HuR and CEACAM1 in discarded human livers that were deemed unsuitable for transplantation.

These findings point to new ways to make liver transplants safer and more successful, Dery said.

“Many donor livers are lost or fail soon after surgery because of damage that happens when blood flow is cut off and then restored,” he said. “By identifying the protective proteins HuR and CEACAM1 that help the liver cope with this stress, our research could lead to treatments that keep more donor livers healthy. This means more patients could receive life-saving transplants, with fewer complications and better long-term outcomes.”

The study has some limitations. For instance, the researchers urge caution in extrapolating the findings to humans because the experimental arm of their work relied only on HuR genetic deletion, which may not be fully applicable to human physiology.

The next step is to test if the protective switches can be turned on in human livers prior to transplantation, Dery said. “This means trying our tools in whole organs kept alive outside the body, to see if we can strengthen the liver and make it more resistant to damage once blood flow is restored,” he said.

Study co-authors are Brian Cheng, Tristan Tibbe, Dr. Siyuan Yao, Megan Wei, Zeriel Wong, Taylor Torgerson, Richard Chiu, Aanchal Kasargod, Dr. Kojiro Nakamura, Monica Cappelletti, Myung Sim, Dr. Douglas Farmer, Dr. Fady Kaldas, and Dr. Jerzy Kupiec-Weglinski of UCLA.

The study was supported by National Institutes of Health (P01 AI120944, R01 DK062357, and R01 AI155856), the National Center for Advancing Translational Science (NCATS) of the NIH under the UCLA Clinical and Translational Science Institute (UL1TR001881), the National Science Foundation Graduate Research Fellowship Program (DGE-2034835).

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