Health Sciences Report Summer 2004

Domino Effect - Traumatic Injury Biochemical Events Life-threatening Syndromes
By Phil Sahm

Portraits by Steve Leitch

Traumatic injury ranks among the most serious health threats in America, killing as many people as a 747-jet airplane crash would every day.

Yet, while it has been glamorized on television, trauma medicine has not captured the headlines for advances in technology and treatment like other areas of medical science. In many respects, the basic precepts of trauma treatment remain the same today as 50 years ago: stop the bleeding, prevent shock, get the patient to a hospital.

The efficiency, technology, and skill with which those fundamentals are delivered, however, have advanced markedly. Another critical area of trauma medicine also has experienced major breakthroughs: research into the complex biochemical events caused by trauma, which often are as serious, or worse, than the initial injury.

Two University of Utah School of Medicine faculty members are unraveling the molecular and biochemical components of traumatic injury. Guy A. Zimmerman, M.D., professor of internal medicine and director of the Program in Human Molecular Biology and Genetics at the Eccles Institute of Human Genetics, is looking at the role of white blood cells in organ failure syndromes that result from trauma. Edward J. Kimball, M.D., assistant professor of surgery, is researching how blood platelet activating factor may cause an inflammatory syndrome when the immune system responds to trauma.

Trauma research is particularly relevant at University of Utah Hospitals & Clinics, which is a nationally certified Level 1 Trauma Center that handles casualties from the most serious situations.

“One of the ironies of trauma is that it can be relatively straightforward to treat,” Zimmerman said. “But it’s really not that simple.”

The stakes in understanding trauma are high: it is the leading cause of death in Americans under the age of 40 and one of the leading causes of death in people over age 65, killing 150,000 annually. Traumatic injuries permanently disable 600,000 people and account for an estimated 37 million emergency room visits and 2.6 million hospital admissions a year. The National Safety Council estimates the cost of treating traumatic injuries at $470 billion per year.

If traumatic injuries affected only bones, skin, or individual organs, the number of fatalities, hospital admissions, and medical costs probably wouldn’t be so staggering. But that’s not the case. Trauma often is accompanied by problems such as sepsis, which is an infection in the bloodstream that can precipitate acute respiratory distress syndrome (ARDS). ARDS is frequently associated with kidney failure and multiple-organ system failure, which can lead to death.

“There is a continuum of responses that causes changes in organs not affected by the trauma,” said Zimmerman, a former critical care physician who last summer served on a trauma research advisory panel to the National Heart, Lung, and Blood Institute, and Department of Defense. “If you have serious trauma, it can set into motion a series of events that causes the lungs and other vital organs to fail,” he said.

For example, within 24-48 hours of suffering a major trauma, patients are at risk for life-threatening ARDS. The lungs become stiff, which dramatically impairs their function and reduces the amount of oxygen in the blood to dangerously low levels. Physicians still do not understand the molecular causes of the syndrome.

Sepsis, historically, has been a pervasive problem in battlefield medicine, and it remains one today, Zimmerman said. When the body suffers wounds, germs and their biochemical components can enter the bloodstream, in addition to causing localized infections. The cellular and molecular responses to the spread of germs and their products throughout the body can be fatal. To repel invading germs, the body responds with shock and dispatches white blood cells to the injury site. But these white blood cells can become unregulated or uncontrolled and attack the body itself, causing organs such as the heart, kidneys, and lungs to fail.

Zimmerman has focused his trauma research in this area: understanding at a molecular level how the white blood cell system works and what makes it go wrong. He’s studying rapidly responding classes of white blood cells that govern their actions in injury and inflammation, particularly the features that determine the pattern of genes they turn on in these conditions.

His laboratory also studies the interactions of white blood cells with endothelial cells, which line the blood vessels, and blood platelets that are key to clotting and tissue repair. Some of these same mechanisms also are relevant to chronic diseases and syndromes of injury, such as atherosclerosis and cancer, which Zimmerman also studies.

Another manifestation of an uncontrolled response to trauma is called System Inflammatory Response Syndrome (SIRS). Kimball, a surgical critical care physician, likens this to the body using “a flamethrower to attack a single cell.”

“When it’s uncontrolled, the immune system is turned on so aggressively it damages tissue and organs that aren’t even involved in the injury,” Kimball said.

When the body responds to trauma, inflammation serves a healthy role by increasing blood flow and bringing more white blood cells to the injury site. One of the many components of inflammation the body produces is blood platelet activating factor (PAF), which is a member of a particular type of lipids. PAF and other lipids have the same effect on inflammation as “gas being poured on a fire,” which, according to Kimball, is healthy when the body produces PAF in the proper amounts as part of the immune response.

PAF’s actions are controlled by an enzyme that binds to it, and then breaks it down, terminating its ability to fuel the fire of inflammation. Sometimes this enzyme, PAF acetylhydrolase, becomes inactivated or overwhelmed by the immune system’s response and cannot break down PAF, so inflammation goes unchecked and results in SIRS or other inflammatory problems.

Kimball, Zimmerman, and Diana M. Stafforini, Ph.D., U associate professor of internal medicine, are investigating how this occurs in sepsis. Stafforini, Zimmerman, Thomas M. McIntyre, Ph.D., U professor of internal medicine, and Steven M. Prescott, M.D., professor of internal medicine and executive director of the University’s Huntsman Cancer Institute, in collaboration with industry, cloned the most important PAF acetylhydrolase several years ago.

Kimball has focused his research on controlling the “over-exuberant” immune response to sepsis and trauma.

Fifty years ago, neither SIRS nor ARDS was known, because people with serious trauma didn’t live long enough for these problems to surface, according to Kimball. The first documented cases of ARDS appeared during the Vietnam War, when soldiers survived wounds that would have been fatal 20 years earlier. But within a few days of being patched up, their lungs would stiffen and start to fail. This in turn led to other organs failing from lack of oxygen.

Similarly, SIRS wasn’t clearly recognized until the 1980s, Kimball said.

In the effort to fight or prevent systemic inflammation or other negative responses to trauma, genetics, as it does in so many other fields of medicine, may play a key role.

“We know very little about the genetic features that control the acute inflammatory system and its responses to injury and trauma,” Zimmerman said. “These variables, together with the nature of the injury, likely determine why one subject with trauma or sepsis develops ARDS or another complication, while another patient with apparently the same injury does not, or has a much milder form.”

Studies have shown that some people produce less PAF acetylhydrolase than others do, according to Kimball. Researchers also have produced synthetic PAF acetylhydrolase and are investigating it as a therapeutic agent for people who have acquired or genetic deficiencies of the enzyme. Clinical trials of investigational medications have shown some success in reducing mortality and shortening stays in intensive care.

“As we understand the biochemistry, we are able to extract therapies,” Kimball said. “Someday we may be able to match people with the best drug.”

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