Jan. 4, 2000 DURHAM, N.C. - A team of Duke University Medical Center researchers has figured out why donated livers can suffer a mysterious injury that damages their ability to perform well once transplanted.
They found out that the cold temperature needed to preserve one set of specialized cells during the time the organ is out of a body is actually producing a chain reaction that ultimately results in the death of a different group of liver cells.
While the findings point to a possible drug to block this process, the study suggests that liver transplant patients should not receive platelet transfusions before their procedures, as some centers routinely do.
The cells in question are called sinusoidal endothelial cells, highly specialized cells that appear only in the liver and which line the tiny blood vessels that form a vast network throughout the organ. Researchers had known that many of these cells become injured or die after the liver is re-attached to its new blood supply in the transplant recipient, but they didn't know the source of this "reperfusion" injury, which can impair liver function.
Immediately after removal from donors, livers are immersed in a special cold solution to preserve the function of hepatocytes, cells who have complex functions, producing as many as 5,000 different proteins. However, the low temperature (1 degree C) required to effectively preserve hepatocytes can also cause the sinusoidal cells -- which act as a detoxifying filter between the blood and hepatocytes -- to become deformed.
Using a unique system in which blood is circulated through a living and functioning liver outside a rat's body, the Duke researchers found that the cells died from a process known as apoptosis, or programmed cell death, and that the blood platelets initiated the apoptosis process.
"Our model showed that the longer the blood circulated through the reperfused liver, the more platelets stuck to the sinusoidal cells," said Dr. Pierre-Alain Clavien, lead researcher and chief transplant surgeon at Duke. "Further analysis of the cells showed that platelets adhered to the sinusoidal cells to trigger apoptosis.
"While we know that platelets are involved in clotting problems in transplants, this study demonstrates another role for platelets in causing problems in transplanted livers," he added.
The results of the study were published Thursday (Dec. 30) in the January issue of the journal Gastroenterology. The first author of the paper is Dr. David Sindram, also of Duke.
For transplant surgeons, the injury and death of the sinusoidal cells is the most important reason for graft failure after transplantation and one of the main challenges to be solved. In this regard, the surgeons face somewhat of a paradox, according to the Clavien.
"On one hand, we must keep the liver cold, which lowers the metabolic rate of the hepatocytes and preserves their function, but now we know that there is something about the period of cold preservation that makes the sinusoidal cells more susceptible to injury," Clavien said. "The cells do not die until they come into contact with blood and oxygen, and then they die very rapidly."
While the researchers do not know for sure what it is about the adhesion of platelets on sinusoidal cells that causes their death, the studies do point to a possible target for therapeutic intervention.
"When we added a sugar that inhibits platelet adhesion to our liver perfusion system, we found a significant reduction in the number of platelets sticking to the sinusoidal cells," Clavien said. "In these particular livers, there was also a corresponding significant reduction in the number of cells undergoing apoptosis."
This suggests that there may be a drug or substance that can be added to the solution used to preserve human livers that would keep platelets from adhering to sinusoidal cells, Clavien said. Aspirin, for example, inhibits platelet aggregation, but because of its blood-thinning properties, it would not be appropriate for someone undergoing a transplant.
While a possible drug may come in the future, Clavien said these findings should cause some centers to rethink their liver transplant protocols.
"Since the liver transplant procedure can involve a lot of blood loss, some centers give their patients platelets before surgery to offset potential losses," Clavien said. "Our data would suggest that this might not be appropriate."
While human livers remain viable outside the body in cold solution for up to 30 hours, liver surgeons know the sooner they can transplant the organ into the recipient, the less injury the organ sustains.
Clavien's group is pursuing what signals the platelets are sending to the sinusoidal cells to get them to commit suicide, as well as the possible role of immune system cells in the blood and the sinusoidal cell apoptosis.
The research was supported by a grant from the National Institutes of Health and from the Duke University department of surgery.
Joining Clavien and Sindram in the study were Duke researchers Dr. Robert Porte, Dr. Maureane Hoffman and Dr. Rex Bentley. Sindram is a research fellow in Clavien's lab and is supported by the Leiden (Netherlands) University Medical Center, the Netherlands Digestive Disease Foundation and the European Society for Organ Transplantation.
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