BLOCKADE OF PANCREATIC PROTEASES—POSSIBLE THERAPEUTIC UTILITY

Despite advances in the understanding of the pathophysiology and treatment of septic shock, knowledge of the complex mechanisms that are involved in the inflammatory response is lacking. We recently obtained evidence that the mechanisms and sequence of events that lead to multi‐organ failure after septic shock include autodigestion by pancreatic enzymes. The intestinal wall generates inflammatory mediators that may be involved in the prolonged inflammation during sepsis. The pancreatic proteases generate and sustain systemic cell activation with consequent organ injury. In septic shock the impact of pancreatic derived inflammatory mediators on preservation of organ function, tissue swelling, inflammation and mortality is unexplored. To determine the role of the inflammatory mediators generated pancreatic enzymes in septic shock, examination of digestive enzyme blockade in the lumen of the small intestine was investigated in adult rats. One hour after systemic endotoxin administration, the small intestine was subjected to intraluminal loading with and without an inhibitor of pancreatic proteases. Without blockade of digestive enzymes, 80% of the animals died within the first 24 hours, while with blockade 70% survived for a period of 4 weeks at which time animals had returned to normal weight gain. These results show a dramatic reduction of mortality rates in endotoxin induced multi‐organ failure by intraluminal blockade of digestive enzymes in the small intestine with possible therapeutic utility.