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Treatments targeting inflammation may prevent deadly condition
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Researchers at Washington University School of Medicine in St. Louis, Northwestern University and other institutions have discovered new clues about early lung transplant failure.
Among organ transplant patients, those receiving new lungs have higher rates of organ failure and death compared to those receiving heart, kidney, and liver transplants. One cause is inflammation that damages the newly transplanted lung.
Now, researchers from Washington University School of Medicine in St. Louis and Northwestern University Feinberg School of Medicine in Chicago have discovered the exact cells that enter and harm the lungs shortly after transplantation. The resulting dysfunction is a major cause of early death after lung transplantation and can lead to organ rejection and death months or years later. This discovery could lead to destructive cell-targeted drug therapies in mice.
“More than 50% of lung transplant patients experience some type of lung injury after transplantation.” Daniel Kreisel, MD, PhDChief of the Department of Lung Transplant Surgery, University of Washington; Barnes Jewish Hospitalwhere they treat patients. “If we can solve this problem, we will increase the success rate of lung transplants.”
The study will be published online May 21 in The Journal of Clinical Investigation.
Kreisel, the study's senior co-author and a professor of surgery, immunology and pathology at the University of Washington, said early lung damage usually occurs within 72 hours after surgery. Once a lung is removed from a donor, it is flushed with cold preservation fluid and placed on ice, where it is cut off from blood and oxygen. This damage usually occurs after the lungs are surgically transplanted and the recipient's blood enters the lungs for the first time. The recipient's white blood cells infiltrate the transplanted lung, causing inflammation that damages the organ's tissues. Affected patients may require prolonged use of a ventilator or even a lung bypass machine in the hospital to give their new lungs a chance to recover.
This condition is a major reason why the success of lung transplants has lagged behind that of other solid organ transplants. Five years after a lung transplant, about half of transplanted lungs are still functioning, according to the U.S. Organ Procurement and Transplant Network. By comparison, the five-year organ survival rate for liver, heart, and kidney transplants is approximately 70 to 80 percent.
“The lungs are unique and fragile organs, and are particularly susceptible to early damage,” said Shimin “Jim” Hsiao, Ph.D., a staff scientist in the Kreisel lab and co-lead author of the study. “This condition is not well understood, so treatment is largely symptomatic. Our research has identified a population of inflammatory cells called monocytes that are key factors in causing inflammation. These We hope that our findings will help develop new treatments for lung transplant patients.”
Researchers studied mice that had undergone lung transplants and found that monocytes were rapidly released from the spleen after the lung transplant. These cells infiltrate the newly transplanted lung and produce a protein called interleukin-1 beta. This in turn invites tissue-damaging white blood cells known as neutrophils.
“Understanding the mechanisms of this damage is important for developing new therapeutics to treat or prevent symptoms in lung transplant patients,” Kreisel said. “We are already developing interleukin inhibitors to treat other inflammatory diseases. The next step is to see whether these types of drugs can suppress the inflammatory cells that cause lung failure. It’s about testing.”
Kreisel shares senior authorship of the study. Dr. Ankit Bharatassociate professor of surgery at Northwestern University. Bharat completed his surgical residency and fellowship training at the University of Washington.
“This study is a fundamental advance in our understanding of early lung injury after transplantation,” said Professor Bharat. “We are excited because this finding builds on our previous work. This study demonstrates a complex but interesting interaction between host immune cells and the newly transplanted lung. This study also introduces a clinically relevant treatment that may extend the lifespan of lung transplant patients.”
In addition to researchers from the University of Washington and Northwestern University, scientists from the University of Virginia at Charlottesville also contributed to the study.
