The Autodigestion Hypothesis in Shock and Multi-Organ Failure: Degrading Protease Activity

Abstract

Shock and multi-organ failure have one of the highest levels of inflammatory markers, morbidities and mortality. The underlying mechanisms are currently unknown and no effective intervention exists. We present evidence for a previously untested mechanism due to autodigestion by the digestive enzymes synthesized in the pancreas and transported in the lumen of the intestine as normal part of food digestion. We summarize experimental evidence in support of the autodigestion hypothesis and a new approach for possible intervention against multi-organ failure that is currently entering clinical trials.

Keywords: Intestine; chymotrypsin; digestive pancreas; elastase; hemorrhagic shock; inflammation; intestinal mucosa; sepsis; trypsin.

Figure 1

Schematic diagram of pancreatic digestive enzyme transport in the small intestine. (Panel A) Compartmentalization of digestive enzymes inside the lumen of a normal intestine by the mucosal barrier with minimal transport into the intestinal wall; (B) escape of digestive enzymes into the wall of an ischemic intestine after elevation of the mucosal barrier permeability, (C) autodigestion of the wall structures by the pancreatic digestive enzymes with loss of intestinal villi and loss of mucosal barrier function. During autodigestion (panel C), the digestive enzymes enter into venules and lymphatics draining the intestine (as long as they are not themselves enzymatically digested), and they pass across the serosa into the peritoneal space. In the intestinal wall the digestive enzymes generate a variety of tissue fragments (e.g. peptide and lipid fragments) that are transported in venules and lymphatics into the portal venous and the central circulation where they act as inflammatory mediators.