Blockade of Pancreatic Digestive Enzymes in the Small Intestine Reduces Mortality in Shock

Shock and multiorgan failure is a major cause of death in hospitals, affecting hundreds of thousands of people in the US alone. The mechanisms that causes the cell destruction during organ failure has remained hidden and consequently no treatments are available today.

We identified as a key player in multiorgan failure the powerful digestive enzymes, the same enzymes responsible for the daily breakdown of food. Digestive enzymes are synthesized in the pancreas and during a meal are transported into the intestine where they mix with food.

During breakdown of food, digestive enzymes need to be contained inside the lumen of the intestine. This is made possible by a barrier for digestive enzymes (but not for food components), the epithelial mucosal barrier lining the intestine.

In shock conditions, like after trauma, puncture of the intestine, or presence of intestinal toxins, this barrier breaks down and consequently digestive enzymes leak out of the lumen of the intestine. They digest the intestine and leak into the systemic circulation where they degrade other tissues.

Enteral Blockade of Digestive Enzymes Reduces Mortality

We tested whether inhibition of the pancreatic digestive enzymes inside the small intestine serves to reduce organ injury and the high mortality during multi-organ failure. In three shock models (hemorrhagic shock, peritonitis shock induced by placement of cecal material into the peritoneum, and endotoxin shock) digestive proteases were blocked inside the lumen of the samll intestine. This intervention served attenuate damage to the intestine and other organs, increase survival after shock. Surviving animals recovered completely and returned to normal weight. Attenuation of autodigestion can be achieved with different protease inhibitors.

These results suggest that the active, concentrated and relatively nonspecific digestive enzymes in the lumen of the intestine play a central role in shock and multi-organ failure, which can be treated with protease inhibitors which are currently available for use in the clinic. Blockade of the digestive enzymes needs to be carried out inside the lumen of the small intestine with minimal delay, before autodigestion has reached irreversible stages of organ dysfunctions.

Blockade of digestive enzymes preserves the intestine.

Small intestine sections in health (top panel) and septic shock without (middle panel) and with (bottom panel) blockade of digestive enzymes by administration of a digestive enzyme inhibitor into the lumen of the intestine. Destruction of the villi by autodigestion (middle) is attenuated by digestive enzyme inhibition (bottom).

See DeLano et al.