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Clues Found To Lung Transplant Failure

Among organ transplant patients, those receiving new lungs face a higher rate of organ failure and death compared with people undergoing heart, kidney and liver transplants. One of the culprits is inflammation that damages the newly transplanted lung.

“More than 50 percent of lung transplant patients experience some lung damage after a transplant,” says Daniel Kreisel, MD, PhD, surgical director of lung transplantation at Washington University and Barnes-Jewish Hospital, where he treats patients. “Eliminating this problem would increase the success of lung transplants.” Kreisel recently was named the G. Alexander Patterson, MD/Mid-American Transplant Chair to honor his innovative work in lung transplantation.

Researchers at Washington University School of Medicine, Northwestern University Feinberg School of Medicine and the University of Virginia, Charlottesville, have uncovered the precise cells that flow into and harm the lung soon after transplant. The resulting dysfunction is the leading cause of early death after lung transplantation and contributes to organ rejection that can lead to death months or years later. The discovery, in mice, may lead to drug therapies that target the destructive cells.

Early lung damage typically occurs in the 72 hours after a patient receives a new lung, says Kreisel, the study’s senior co-author. When a lung is removed from a donor, it is flushed with a cold preservation fluid and placed on ice, where it is deprived of blood and oxygen. As the recipient’s blood enters the lung for the first time, white blood cells trigger inflammation that harms the organ’s tissue. Affected patients can require extended time on a ventilator or lung bypass machine to give the new organ a chance to recover.

This condition is a big reason why the success of lung transplants trails behind other solid-organ transplants. Five years after transplantation, about half of the transplanted lungs are still functioning, according to the U.S. Organ Procurement and Transplantation Network. This compares with five-year organ survival rates of about 70 to 80 percent for liver, heart and kidney transplants.

“Lungs are unique, fragile organs that are particularly susceptible to early damage,” says Hsi-Min “Jim” Hsiao, PhD, a staff scientist in Kreisel’s laboratory and the study’s co-first author. “Treatment is largely supportive, as the condition is not well-understood. Our research identifies a population of inflammatory cells called monocytes that are key instigators to the inflammation. We are hopeful that these findings will help with the development of new therapies for lung transplant patients.”

Studying mice that had undergone lung transplants, the researchers found that monocytes are rapidly released from the spleen after lung transplantation. These cells infiltrate the newly transplanted lung and then produce a protein called interleukin 1 beta, which, in turn, invites in the tissue-damaging white blood cells known as neutrophils.

“Understanding the mechanisms of this damage is important in developing novel therapeutic agents to treat or prevent the condition in lung transplant patients,” Kreisel says. “We already have interleukin-inhibitor drugs for treating other inflammatory diseases. The next step is to test whether this type of drug can tamp down on the inflammatory cells that cause lung failure.”

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