The Autodigestion Hypothesis for Shock and Multi-organ Failure
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An important medical problem with high mortality is shock, sepsis and multi-organ failure. They have currently no treatments other than alleviation of symptoms. Shock is accompanied by strong markers for inflammation and involves a cascade of events that leads to failure in organs even if they are not involved in the initial insult. Recent evidence indicates that pancreatic digestive enzymes carried in the small intestine after mixing with ingested food are a major cause for multi-organ failure. These concentrated and relatively non-specific enzymes are usually compartmentalized inside the intestinal lumen as requirement for normal digestion. But after breakdown of the mucosal barrier they leak into the wall of the intestine and start an autodigestion process that includes destruction of villi in the intestine. Digestive enzymes also generate cytotoxic mediators, which together are transported into the systemic circulation via the portal venous system, the intestinal lymphatics and via the peritoneum. They cause various degrees of cell and organ dysfunction that can reach the point of complete organ failure. Blockade of digestive enzymes in the lumen of the intestine in experimental forms of shock serves to reduce breakdown of the mucosal barrier and autodigestion of the intestine, organ dysfunctions and mortality.
KeywordsPancreatic digestive enzymes Trypsin Mucin Epithelium Sepsis Inflammation Unbound free fatty acids
We thank Erik Kistler, Alex Penn, Angelina Altshuler, Frank A. DeLano for many discussions regarding the autodigestion hypothesis. Supported by NIH Grants HL 67825 and GM 85072 and by an unrestricted gift from Leading Biosciences Inc. The authors thank Mr. Frank A. DeLano for preparation of Fig. 4.
Conflict of interest
G. W. S.-S. is scientific advisor to Leading Biosciences Inc. and owns equity in InflammaGen, a company by Leading Bioscience Inc., which develops therapy for shock patients.
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