New Data from Animal Studies Shows Dramatic Reduction of Mortality in Life-Threatening Shock by Inhibiting Body's Own Aggressive Digestive Enzymes.

Novel Approach Targets Trigger Mechanism for Inflammation by Auto-Digestion before It Launches Lethal Cascade

SAN DIEGO -- Death from heart, lung and kidney failure during shock due to inadequate blood flow can be prevented by an unusual new experimental treatment that inhibits the aggressive enzymes that are produced in the body to digest food, according to research results released here today at "Research Expo: Igniting Innovation," sponsored by the University of California at San Diego Jacobs School of Engineering.

Geert W. Schmid-Schonbein, Ph.D., presented data from recent animal studies conducted in his laboratory at UCSD in an abstract titled "The Auto-Digestion Hypothesis: Blockade of Pancreatic Digestive Enzymes in the Lumen of the Intestine During Hemorrhagic Shock Reduces Mortality." For the first time, studies showed that blockade of the digestive enzymes during shock leads to long-term survival.

"The results show a dramatic reduction of mortality in hemorrhagic shock induced multi-organ failure," said Dr. Schmid-Schonbein. "Pending further research, this treatment holds promise for future clinical application, particularly in emergency rooms and before high-risk surgeries."

An estimated 1 million cases of various types of shock are treated annually in U.S. hospital emergency rooms and the condition has a high fatality rate.

Schmid-Schonbein, professor of bioengineering and adjunct professor of medicine at UCSD, has been studying inflammation for more than 30 years. His current research is being funded, in part, by Leading Ventures (www.leadingventures.com), a San Diego-based venture capital firm. Its senior managing director, John Rodenrys, also presented during the Research Expo at UCSD which was attended by more than 600 people.

In 1997, Schmid-Schonbein achieved a breakthrough in laboratory studies on the cause of the body's inflammatory cascade and the factors that turn this normal tissue-healing biological process into a virulent attack on the body's normal tissue.

In shock, a normal barrier of protection by the cell lining fails and the digestive enzymes escape into the wall of the intestine, starting auto-digestion, inflammation, production of cytotoxic mediators, and multi-organ failure.

Administering a drug to inhibit the body's digestive enzymes at the trigger point of the cascade is a new approach Schmid-Schonbein and his research team began pursuing in 2000. The researchers advanced from the lab to animal studies to test and fine-tune their approach.

The abstract presented at the Jacob's School conference was based on the latest research using rodent models of human hemorrhagic shock.

In their latest studies, Schmid-Schonbein and his team induced shock in 24 lab rodents, all of which were then treated with therapies that mirror the emergency room care given to many human patients who suffer shock.

A total of 12 of the 24 lab rodents in shock were also treated with an experimental digestive enzyme inhibitor. Their digestive enzyme activity in the lumen of the intestine was blocked temporarily. Ten of the twelve (83%) treated animals survived.

However, only three of the twelve "untreated" (25%) animals in shock survived. The other nine animals died from organ failure within 12 hours. Although these "untreated" animals did not receive treatment to inhibit their digestive enzymes, they were given basic shock care.

The next step before possible clinical studies with human patients who have suffered shock will be determined by the results of current laboratory investigations with pigs at the University of California at Irvine being conducted by Schmid-Schonbein's collaborator, surgeon David Hoyt, M.D.

In the pig studies, the scientists are fine-tuning procedures and also conducting experiments to identify when the experimental treatment will be the most effective in saving lives. The findings will be relevant to the emergency care of human patients in shock.

"Our data indicate that the earlier the treatment occurs, the better the chances for survival," said Schmid-Schonbein. "But the good news from the current research is that there is a finite window of opportunity for the treatment to be effective."

Schmid-Schonbein and his team's discovery of the "auto-digestion" process and their recent positive findings are based on National Institutes of Health funded basic research to determine the origin of the inflammatory cascade that causes organ failure and death.

Collaborating with Schmid-Schonbein are: Frank Delano, Erik Kistler, M.D. Ph.D., Alex Penn, Ph.D, UCSD; David Hoyt, M.D. Head, Department of Surgery, UC Irvine, and Tony Hugli, Ph.D. and Marlene Kawahara, Torrey Pines Institute for Molecular Studies, San Diego.

UCSD has granted a license to a San Diego startup company, InflammaGen, to commercialize Schmid-Schonbein's discoveries about auto-digestion. InflammaGen is funded by Leading Ventures.

"This treatment has many potential uses including soldiers injured on the battlefield, patients admitted to the Emergency Room with severe injuries, patients undergoing major surgery such as coronary artery bypass surgery and patients in intensive care," said Leading Ventures' Rodenrys (www.leadingventures.com).