Scientists discover promising new path for treating traumas

October 25, 2009

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A deadly cascade: How histones cause life-threatening bleeding.

(PhysOrg.com) -- A discovery by scientists at the Oklahoma Medical Research Foundation could help save lives threatened by traumatic injuries like those sustained in car crashes or on the battlefield. The work also holds potential for treating severe infectious diseases and diabetes.

In a paper published online today in the advance edition of the scientific journal Nature Medicine, OMRF researcher Charles Esmon, Ph.D., with co-authors Florea Lupu, Ph.D., and Jun Xu, Ph.D., has cast new light on how proteins called histones can enter the bloodstream and begin to kill the lining of blood vessels, resulting in uncontrolled internal bleeding. Building on this work, Esmon and a team of collaborators have discovered an antibody that could counter this deadly process.

"This discovery could open the door to new ways to treat soldiers hurt in IED attacks, gunshot wound victims and people who suffer a traumatic injury," said Esmon, who holds the Lloyd Noble Chair in Cardiovascular Biology at OMRF. "When we realized that histones were so toxic, we immediately went to work looking for a way to stop their destructive tendencies."

Inside the cells, histones perform an important function, keeping DNA coiled and compressed inside the nucleus. But the OMRF researchers found that when cells become damaged and burst—either through injury, infection or diseases such as diabetes—histones can enter the bloodstream and begin to kill the lining of blood vessels. This results in uncontrolled internal bleeding and fluid build-up in the tissues, which are life-threatening.

Working with Temple University's Marc Monestier, M.D., Ph.D., the group discovered antibodies (pathogen-fighting proteins produced by the body's immune system) that can block the histones' ability to kill. "When a patient is suffering from severe bleeds, these antibodies could prevent multi-organ failure," said Esmon, who is a member of the National Academy of Sciences.

The researchers have already tested the antibodies in pre-clinical trials, where they showed promising results and no adverse effects. A potential future step, said Esmon, would be human trials.

"The implications for this discovery are staggering," said OMRF President Stephen Prescott, M.D. "Dr. Esmon and his colleagues have not only found a new key player in cardiovascular injuries and disease, but they've taken this work and transformed it into a potential treatment for severe trauma, diabetes, pneumonia and any other condition that results in tissue death."

The work, said Prescott, also helps lay a foundation for future research. "These findings offer some clues as to why people suffering from one traumatic injury often experience a catastrophic 'cascade' of secondary traumatic events," he said. "If we can figure out how to control the initial injury, perhaps that will stop the domino effect that so often follows."

Esmon's research has already yielded two FDA-approved drugs. His work with OMRF researcher Fletcher Taylor, M.D., led to the creation of Xigris, a treatment for severe sepsis. And with his wife and colleague, Naomi Esmon, Ph.D., he helped create Ceprotin, a therapeutic for patients suffering from a life-threatening protein deficiency.

Source: Oklahoma Medical Research Foundation