Study May Improve Survival Of Transplanted Livers

About 5,000 liver transplants are performed annually in the United States, and a key factor ensuring success is maintaining a healthy donor organ that can function effectively in the recipient. However, transplanted livers typically incur substantial damage when blood flow is restored to the organ after the transplant.

This damage occurs when ischemic, or oxygen-deprived, tissue is re-introduced, or reperfused, to adequate blood flow. The study, to be published in the June issue of the journal Hepatology, showed that use of nitric oxide during reperfusion protected cultured rat liver cells, or hepatocytes, from cell death typically occurring as a result of reperfusion stress.

"Reperfusion stress precipitates the death of the tissue, but our results suggest that the way we reperfuse the liver can reduce injury to it," said Dr. John Lemasters, professor of cell and developmental biology at UNC and senior investigator for the study.

Preventing such damage is relevant in liver transplants and essential to the success of organ transplantation in general, UNC researchers said.

This injury also is central to the nature and development of shock, stroke and heart attacks, Lemasters added.

Cell death due to reperfusion stress results from damage to the hepatocyte's mitochondria, the cellular site of generation for the primary energy molecule in a cell, called adenosine triphosphate (ATP). This damage, known as mitochondrial permeability transition (MPT), opens up the mitochondria to small molecules entering the organelle and interrupting generation of ATP. Then, cell death occurs.

Nitric oxide exerted its protective effects in the study's model by blocking the MPT-based injury to the hepatocyte, the study showed. "Our cell culture model mimics severe ischemia, and nitric oxide was still effective in blocking cell death," said Dr. Jae-Sung Kim, the primary study author and assistant professor of cell and developmental biology.

Use of nitric oxide after cold storage of the donated organ may help maintain normal liver function after the transplant, the study indicated.

"Nitric oxide protects the liver during the reperfusion phase, after ischemia has occurred, and this means we can intervene in a meaningful way," said Lemasters. "We can treat after disease onset."

Because it reacts rapidly with oxygen, nitric oxide can cause damage to the transplanted liver at certain levels. Therefore, the appropriate concentration of nitric oxide is vital to guarantee its protective effects, the scientists said.

The researchers also discovered that nitric oxide exerts its protective effects by stimulating the liver cells to produce cell-signaling molecules - cGMP, which activates protein kinase G - required for other protective agents in the body to function.

"Our result suggests that cGMP analogues or other agents that elevate cGMP levels in liver cells may also induce this protective effect," said Lemasters.

One of these agents, atrial natriuretic factor, has been shown to protect against the reperfusion stress that occurs after a heart attack. "Our next step is to test our hypothesis that atrial natriuretic factor will be protective against ischemia-reperfusion injury in the liver," said Kim.

The researchers also want to determine if nitric oxide can be protective in an animal liver transplant model.

Drs. Shigetoshi Ohshima and Peter Pediaditakis, postdoctoral researchers, also were authors on the study.

This research was supported by grants from the National Institutes of Health.