Possible cause and treatment for shock uncovered by UC San Diego bioengineers

Researchers prevented shock and multiple organ failure in experimental animals by blocking powerful pancreatic digestive enzymes in the intestine, according to studies by bioengineers with the Jacobs School of Engineering at the University of California, San Diego. This fundamental breakthrough could lead to therapies to prevent and treat ischemic shock in people who experience shock following blood loss from traumatic injury or high-risk surgery. The work also provides clues into the cellular mechanisms that lead to shock.

The research report titled "Generation of In Vivo Activating Factors in the Ischemic Intestine by Pancreatic Enzymes" will be published in the Proceedings of the National Academy of Sciences on February 15. The principal investigator of the study is Geert Schmid-Schoenbein, professor of bioengineering at the Jacobs School of Engineering, and the work was funded by the National Heart, Lung, and Blood Institute. The research was conducted with Hiroshi Mitsuoka and Erik Kistler in Schmid-Schoenbein's Microcirculation Research Laboratory.

Ischemic shock occurs when blood pressure falls after blood loss or deep anesthesia. Vital organs are poorly perfused and literally starved of oxygen. Early symptoms include cold, clammy skin, mental confusion and inadequate production of urine. But shock can quickly lead to multiple organ failure and even death.

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These symptoms are induced when activators in the blood stream turn on various cardiovascular cells including leukocytes (white blood cells) and endothelial cells (blood vessel walls). Abnormal interactions between leukocytes and endothelial cells produce inflammation, alter blood flow, and finally cut off delivery of oxygen to the organs.

But never before have researchers found strong evidence for the source of the cell activators. "The pancreas produces potent enzymes that can digest any tissueÐeven our own. These enzymes are regularly released into the intestines to digest our food," said Schmid-Schoenbein. "Our theory is that when blood pressure falls sharply in the intestine, pancreatic enzymes in the intestine start to escape from the lumen of the intestine (where they digest food), into the wall of the intestine (where they don't belong). These enzymes produce and release dangerous activators into the blood stream, initiating a cascade of events leading to multiple organ failure."

To test their theory, the researchers surgically produced shock in rats. Control rats were given no treatment. But the researchers injected a broadly acting pancreatic enzyme inhibitor* into the lumen of the small intestine of the subject rats prior to inducing shock in the animals. The control rats experienced classic symptoms of shock including a drop in blood pressure, inflammation and multiple organ failure. The treated rats experienced much less pressure reduction, no activation of leukocytes or endothelial cells, no appearance of cell activators in the circulation, no inflammation, and no significant organ injury.

"We have clearly found a key source of the activators that lead to shock. This is a completely new result," said Schmid-Schoenbein. "With this knowledge, we can begin to explore effective treatments with the possibility of preventing the death of thousands of people each year."

Schmid-Schoenbein's group is testing the procedure with different types of enzyme inhibitors. He is also taking initial steps to plan human trials.

*The inhibitor used was 6-amidino-2-naphtyl p-guanidinobenzoate dimethanesulfate,ANGD, 0.37 mM, also known as nafamostat mesilate or Futhan.

Images: High-resolution image of activated and inactivated white blood cell available on the web at www.soe.ucsd.edu/events/releases.html.