For decades, treating strokes has been based on quickly restoring blood flow, in hopes of minimizing damage to brain tissue. But patients rarely seek medical attention soon enough to be helped before the damage is done.
A new line of research shows the damage that occurs in the early hours after a blood clot has lodged in the brain can be blocked by an enzyme on the surface of white blood cells. These white blood cells are normally protective during emergencies such as cuts and infections, but their accumulation in the brain in stroke can be devastating.
Researchers at the University of Michigan Cardiovascular Center believe these white blood cells are capable of “self-trafficking,” that is, responding to injury on their own, eventually overwhelming tissue. The enzyme on the white blood cell surface acts as a brake under the white cell’s own control and may prevent the cells from causing more harm than good.
The research, funded in part by the A. Alfred Taubman Medical Research Institute, gives clues to treating a leading cause of death and disability in the United States.
“What this research shows is how white blood cells regulate their own ability to migrate into tissue,” says senior author David J. Pinsky, M.D. (pictured), the J. Griswold Ruth M.D. and Margery Hopkins Ruth Professor of Internal Medicine and Chief of Cardiovascular Medicine at the University of Michigan (U-M), as well as a director of the U-M Cardiovascular Center, and a Taubman Scholar.
“They are not just called into a zone by blood vessel wall cells, but it turns out they have a voice too. They have a voice in deciding where they ultimately go.”
Strokes are caused by tiny blood clots that break off from the lining of a blood vessel, blocking the flow of blood in the area and leading to death of brain tissue. About 80 percent of strokes are ischemic, which is due to a blocked artery.
The team’s research, conducted in mice, showed dead and dying brain tissue release intracellular contents into the blood, including an energy molecule called ATP.
“Based on our findings, we believe that this ATP signals to white blood cells to home to the ischemic brain,” says co-author Matt Hyman, who led the research as part of his doctoral work at the University of Michigan.
“Interestingly it appears that the leukocytes (white blood cells) have a protein on their surface that allows them to turn this ATP signaling on and off and thus control their own fate,” Hyman says.
The initial ischemic injury to brain tissue, according to the U-M study, is from the lack of blood flow, but the injury worsens due to the accumulation of the white blood cells.
“In the fighting off of infection, our white blood cells release toxins to attack germs and clean up tissue. In the case of a stroke, those same destructive compounds are released, but there’s collateral damage to nerve cells and other cells in the region,” says Pinsky.
Strokes are a serious public health problem and leading cause of disability. The cascade of events during stroke can lead to paralysis, inability to speak, and cognitive problems. Strokes kill 160,000 people a year, making them the third most common cause of death in Western countries.
Current therapies to treat stroke include thrombolytic drugs that can restore blood flow, but can cause bleeding in the brain and elsewhere.
While Pinsky is cautious about speculating, he notes that any time medical science understands a system better, it can lead to new ideas for targeting disease.
Pinsky and his team are using Taubman Institute funding to study the role of ectoenzymes, proteins that protrude from the surface of the cells that line every blood vessel in the body. Specifically they have zeroed in on a single ectoenzyme that can stop the formation of a clot by interfering with the signals that blood platelets send out during the very early stages of clot formation.
The strategy could conceivably lead to making the enzyme, or a portion of it, to be given in an urgent care setting to abort clot formation. It could be a low-risk solution to unwanted clots.
Illustration: University of Michigan Health System.
University of Michigan Health System News Release (05/07/09)
Abstract (Journal of Clinical Investigation; Vol. 119, Issue 5, 1136-1149 (05/01/09))