UW News

January 19, 2006

Controlling evolved response can save tissue

Most biomedical researchers work in tandem with the process of evolution, tracing the history of an organism’s development over eons. But Dr. John Harlan has to work against evolution.

Harlan and his colleagues study the natural inflammatory responses that animals and humans have after injuries. Their specialty is ischemia, which is the lack of oxygen in tissue that is caused by a massive loss of blood or stoppage of blood flow due to a major trauma, for instance, or a heart attack.

Ischemia can cause tissue to start to die off, as the cells begin to run out of oxygen necessary for vital processes. That’s why CPR is so important to a person who isn’t breathing — a lack of oxygen can cause brain tissue to die, or other damaging injuries.

But rebounding quickly from ischemia can also be harmful — the rapid influx of blood and oxygen to dying tissue can cause something called ischemia-reperfusion injury, which is when the body rejects the life-saving fluids. Trauma victims with massive blood loss and shock, for example, will sometimes respond poorly to restoration of blood flow, and the body’s own inflammatory response — the driver of the ischemia-reperfusion injury — can lead to multiple organ failure and death.

An inflammatory response in such a situation seems like it’s the opposite of how the human body should react. After all, if an influx of oxygenated blood would help save damaged tissue, it seems like the body would welcome the return of blood flow. But that’s where evolution comes into the picture, Harlan explained.

“Organisms probably evolved such that dying tissue was never meant to be rescued from ischemia,” said Harlan. “That’s why there’s this inflammatory response to the rescuer.”

White blood cells, also known as leukocytes, protect the body from infections. But they also drive inappropriate inflammation, like the negative response after a resuscitation from shock. Similar injuries can strike patients after a heart attack, a stroke, severe burns, organ transplants, and even coronary artery bypass surgery.

Harlan and his colleagues, Dr. Robert Winn, research professor of surgery, and Dr. Nicholas Vedder, professor of surgery and chief of plastic surgery at Harborview Medical Center, have focused on blocking white blood cell responses after reperfusion. They have tested drugs called adhesion antagonists, which prevent white blood cells from binding to blood vessels and entering tissue during an inflammatory response.

Early tests in animal models showed much promise, with the drugs drastically reducing the damage from ischemic reperfusion. However, researchers did not find a reduction in death from human clinical trials in blood-loss victims, or those suffering from stroke or heart attack.

That was a few years ago, and Harlan and Winn went back to the drawing board to see why the drugs might work differently in people than in animals.

“We went from the bench to the clinic, and now we’re going to go back to the bench,” said Harlan. “We’d like to find out why our pre-clinical experiments showed so much promise, but didn’t have the desired benefit in clinical trials.”

Their research has shown that if oxygen loss to tissue is prolonged, then adhesion antagonist drugs no longer work when you restart blood flow. With longer periods of oxygen loss, the cells in tissue can begin to die off, in a process called apoptosis. So now, Harlan and Winn are looking at a new type of drug that may help block apoptosis as well as reduce inflammation. This could lead them to a two-pronged approach, keeping cells from dying off until blood flow is restored and preventing a dangerous inflammatory response.

If Harlan and his collaborators are successful, the findings could help reduce the risk of death and injury from the body’s own well-evolved inflammatory response.

Harlan will discuss his research on leukocyte adhesion antagonists and inflammation in general at this month’s Science in Medicine Lecture, Damage Control: Limiting Tissue Injury in Inflammation. The lecture will be held from noon to 1 p.m., Thursday, Jan. 26, in Hogness Auditorium, room A-420 of the UW Health Sciences Center. Harlan is the Clement A. Finch Professor of Hematology and an adjunct professor of pathology at the UW, as well as the associate medical director for blood services and chief of hematology/oncology at Harborview.