Enzymes may leak outside intestines and cause deadly condition

By Nathan Seppa

Web edition: January 23, 2013
Print edition: February 23, 2013; Vol.183 #4 (p. 10)

Digestive enzymes that escape from the intestines into adjacent tissues and the bloodstream may be a key player in triggering shock, the dangerous condition that sometimes occurs after major medical trauma. A new study finds that giving enzyme inhibitors to rats in the throes of shock can alleviate the potentially lethal condition.

The findings could shed some much needed light on shock, which typically shows up as the end result of some other medical problem such as hemorrhage, sepsis, a heart attack or a systemic allergic reaction called anaphylaxis. In all cases, blood pressure plummets, sabotaging circulation and threatening tissue viability.

The new study, in the Jan. 23 Science Translational Medicine, suggests that digestive enzymes play a role in this crisis. The enzymes normally help break down food, but they need to be confined to the ducts in the pancreas, where they are made, or the small intestine, where they digest food. If not, the enzymes can digest a person’s own tissue.

A mucosal lining in the intestines keeps the enzymes from escaping the gastrointestinal tract and from damaging the intestines themselves. But hemorrhage, sepsis and other conditions disrupt blood flow to the intestinal wall and hinder maintenance of this barrier, says Geert Schmid-Schönbein, a bioengineer at the University of California, San Diego in La Jolla. If digestive enzymes stray into the rest of the body, he hypothesizes, they could damage vital organs and trigger massive inflammation.

Schmid-Schönbein and his colleagues tested this scenario by inducing shock in rats through blood loss, with bacterial endotoxin poisoning in the intestines to replicate sepsis, and by infecting the peritoneum — the space around the intestines — with fecal matter to mimic intestinal leakage, as might happen with trauma. All three models led to a breakdown of the mucosal barrier in the intestines of the rats, unleashing digestive enzymes into intestinal tissues, the bloodstream and beyond, Schmid-Schönbein says.

One hour after the shock-inducing procedures, some rats were treated with enzyme blockers injected into the small intestine and, in some, the peritoneum. Over three months, most of these treated rats survived, whereas most of the untreated rats with shock died of heart or respiratory failure. The treated rats also showed less intestinal damage, indicating limited barrier breakdown.

“This is a very intriguing approach,” says Asrar Malik, a pharmacologist at the University of Illinois at Chicago College of Medicine. “It’s very inclusive, covering three models of experimental shock.”

The new study should set the stage for tests in larger mammals, Malik says, and if successful, in people — especially patients with sepsis, a leading cause of death for people in intensive care units. Sepsis is a whole-body inflammatory state typically brought on by bacterial endotoxins. Fatality rates range from 20 to 35 percent, and the death risk rises if a patient goes into shock.

“This is relevant to future treatment of that disease,” Malik says. “The treatment possibilities are there.” Enzyme blockers called protease inhibitors are already approved to fight HIV.

There is an anecdotal precedent for treating shock with enzyme blockers. In 2010, an emergency course of enzyme inhibitors apparently rescued a patient who had developed sepsis and gone into shock, Schmid-Schönbein says. He was in Taiwan delivering a lecture and got a call later that day about the patient. The man had received a successful heart transplant four years earlier but was dangerously ill with septic shock unrelated to the transplant. Doctors gave him a course of enzyme inhibitors and, after other treatment that included intestinal surgery, he recovered, researchers reported in Transplantation Proceedings in 2012. “The guy is now walking around Taipei,” Schmid-Schönbein says.