August 21, 2003
Learning how lungs for transplant get damaged
Sometimes transplanted organs do not thrive in their new homes. Inflammation is one cause of organ rejection.
When a lung is preserved and then transplanted into a new human being, it is not uncommon that it will get inflamed when blood flow is restored to the lung.
This is what is known as lung ischemia-reperfusion injury, also called lung reperfusion injury. Ischemia is a decrease in blood supply to a bodily organ. Reperfusion is the restoration of blood flow.
Lung reperfusion injury happens to about 25 percent of lung transplant patients, according to Dr. Michael Mulligan, an associate professor in the Department of Surgery, Division of Cardiothoracic Surgery.
“A lot wasn’t known about this type of injury even five years ago,” he said.
Mulligan has been researching this particular injury for six years. Specifically, he is researching the role of calcineurin, a protein, in lung reperfusion injury.
“We’ve been trying to figure out what the ‘off’ switch is for this flurry of responses,” Mulligan said.
So far, Mulligan, along with his research assistants, has been making progress. They have demonstrated what cell types are important and have been able to break down the lung into its constituent cell populations, along with other discoveries.
“We’ve identified requirements for six different cytokines; we have characterized the key coordinating cell in the whole reaction, and we have defined sequential requirements for three different transcription factors,” Mulligan said.
Mulligan was part of a research team in 2001 that did a study using rat lungs. The findings were published in the Journal of Thoracic and Cardiovascular Surgery.
Calcineurin inhibitors were already known to reduce experimental reperfusion injury in the liver, brain, heart, kidney, and small bowel. Mulligan’s group set out to determine whether calcineurin inhibitors were similarly protective against lung ischemia-reperfusion injury.
To conduct the study, the left lungs of male rats were rendered ischemic for 90 minutes and reperfused for as long as four hours. Treated animals received cyclosporine A, an immunosuppressive drug obtained from certain soil fungi and used mainly to prevent the rejection of transplanted organs, or tacrolimus, a chemical that has strong immunosuppressive activity and prevents the activation of T-lymphocytes in response to stimulation. The animals received these drugs six hours before ischemia, at reperfusion, or two hours after reperfusion.
Treatment with cyclosporine or tacrolimus six hours before reperfusion showed the best results, with injury being reduced by 54 and 56 percent relative to the control animals. Administration of cyclosporine or tacrolimus at the time of reperfusion or two hours into the reperfusion period offered little or no protection.
The researchers concluded that the mechanism of these protective effects may involve the inhibition of nuclear factor B, a central transcription factor mediating inflammatory injury, according to the study.
Mulligan is still “working upstream” to get to the root of the problem. He said he believes he is coming close.
“Being so close to a clinical trial,” Mulligan said, “I think we can see this materialize in the next two to three years. Some of the treatment we’ve come up with already has shown the potential to reduce reperfusion injury by 80 percent.”
Mulligan will speak on “The Role of Calcineurin in Lung Reperfusion Injury” at noon on Thursday, Sept. 18, in Turner Auditorium, D-209, Health Sciences Building. The lecture is open to everyone. The presentation is the first in the 2003-2004 Science in Medicine series, sponsored by the School of Medicine’s Office of Research and Graduate Education, and is one of the “new investigator” lectures in the series.
Mulligan received his M.D. from the University of Connecticut in 1989. Before he came to the UW in 1999 as an assistant professor, he was a John Alexander fellow in general thoracic surgery at the University of Michagan. He completed his residency at Columbia-Presbyterian Medical Center in New York from 1992-95.
He has earned numerous honors, including an award for best presentation in 1999 from the Seattle Surgical Society, first place in a research competition given by the Michigan Society of Thoracic and Cardiovascular Surgeons in 1996, and the John K. Stevenson Faculty Teacher of the Year Award from the UW Department of Surgery in 2000.
Mulligan gained local and national attention after the terrorist attacks in 2001 for a trip he made that day by plane and helicopter to bring donated organs from Alaska to Seattle for transplant.
