Biomechanical aspects of the auto-digestion theory.

Increasing evidence suggests that most cardiovascular diseases, tumors and other ailments are associated with an inflammatory cascade. The inflammation is accompanied by activation of cells in the circulation and fundamental changes in the mechanics of the microcirculation, expression of pro-inflammatory genes and downregulation of anti-inflammatory genes, attachment of leukocytes to the endothelium, elevated permeability of the endothelium, and many other events. The evidence has opened great opportunities for medicine to develop new anti-inflammatory interventions. But it also raises a fundamental question: What is the origin of inflammation? I will discuss a basic series of studies that was designed to explore trigger mechanisms for inflammation in shock and multi-organ failure, an important clinical problem associated with high mortality. We traced the source of the inflammatory mediators to the powerful digestive enzymes in the intestine. Synthesized in the pancreas as part of normal digestion, they have the ability to degrade almost all biological tissues and molecules. In the lumen of the intestine, digestive enzymes are fully activated and self-digestion of the intestine is prevented by compartmentalization in the lumen of the intestine facilitated by the mucosal epithelial barrier. Under conditions of intestinal ischemia, however, the mucosal barrier becomes permeable to pancreatic enzymes allowing their entry into the wall of the intestine. The process leads to auto-digestion of the intestinal wall and production of inflammatory mediators. The hypothesis that multi-organ failure in shock may be due an auto-digestion process by pancreatic enzymes is ready to be tested in a variety of shock conditions.