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Strategy May Improve Survival after Shock

Scientists found that blocking digestive enzymes in rat intestines increases survival, reduces organ damage and improves recovery after shock. The innovative approach may lead to therapies to improve patient outcome following shock, sepsis and multiorgan failure.

Shock is a life-threatening condition in which blood pressure drops and not enough blood and oxygen can get to organs. It has different causes — including heart attacks, sepsis and internal bleeding — and often results in multiple organ failure. Strong markers for inflammation have been associated with shock. Past studies suggest that this inflammation involves the digestive system — the small intestine in particular — but the mechanism isn’t well understood.

Powerful enzymes that digest food are produced by the pancreas and transported to the lumen (inner open space) of the small intestine. Normally, these enzymes are contained within the lumen by the mucosal barrier. However, injury to the intestine can break down the barrier and allow enzymes to cross from the lumen into the intestinal wall. The enzymes then “self-digest” the intestinal tissue, which can lead to inflammation throughout the body and multiorgan damage.

Past work led by Dr. Geert Schmid-Schönbein of the University of California, San Diego, showed that blocking enzymes in the intestinal lumen reduces inflammation and multiorgan failure in animal models of shock. In the new study, Schmid-Schönbein’s team set out to test whether enzyme inhibitors can improve long-term survival.

To mimic the complex condition in people, the researchers used rat models of 3 different types of shock: hemorrhagic (bleeding), septic (infection) and toxic (bacterial toxin). An hour after shock induction, 1 of the 3 enzymatic inhibitors was injected directly into the small intestinal lumen. The work was partly funded by NIH’s National Heart, Lung and Blood Institute (NHLBI) and National Institute of General Medical Sciences (NIGMS). Results appeared on January 23, 2013, in Science Translational Medicine.

The researchers found that all 3 inhibitors greatly improved survival from all 3 types of shock. Overall, almost 86% (60 out of 70) of treated rats survived, compared to about 17% (12 out of 72) of untreated rats. Survivors recovered within 14 days of shock induction. Nonsurvivors had cardiac and respiratory arrest within 12 hours.

After inhibitor treatment, fewer enzymes passed from the lumen into the intestinal wall in all types of shock. This resulted in less self-digestion and damage to the intestine, heart and lungs.

“Organisms rely on full containment of the digestive enzymes in the small intestine. The moment the intestinal mucosal barrier is compromised, the digestive enzymes escape and then we are no longer digesting just our food, but we may be digesting our organs,” says Schmid-Schöbein.

Future studies will involve clinical trials testing enzyme inhibitors in shock patients. One of the inhibitors used in this study — tranexamic acid — is already approved for use in people.

— by Miranda Hanson, Ph.D.

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