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Bioengineering Seminar Series: Geert W. Schmid-Schönbein
Friday, April 2, 2010
11:00 a.m.
Room 2110, Chemical and Nuclear Engineering Bldg.
For More Information:
Professor Helim Aranda-Espinoza

The Auto-digestion Hypothesis in Acute and Chronic Inflammation: A Case for Multi-organ Dysfunction and Type II Diabetes

Presented by Geert W. Schmid-Schönbein, Ph.D.
Microcirculation Laboratory
Department of Bioengineering
Institute for Engineering in Medicine
University of California San Diego

One of the important opportunities for bioengineering is to contribute to the analysis of human disease. A convenient entry point for analysis of disease is the study of inflammation. Inflammation consists of a cascade of reactions in living tissues that serve to repair injured tissue. An increasing body of evidence shows that distinct markers for inflammation accompany most chronic and acute human diseases. An important question is therefore the mechanism for tissue injury that leads to inflammation in the first place. Our work is focused on this important question and I will discuss acute physiological shock and multi-organ failure, a condition associated with high mortality, and Type II Diabetes, a chronic condition with high morbidity.

We recently demonstrated in shock and multi-organ failure that leakage of pancreatic digestive enzymes from the intestine causes enzymatic injury to the intestine, i.e. auto-digestion. Fully activated in the intestine as part of normal digestion, these powerful degrading enzymes are usually compartmentalized in the lumen of the intestine by the mucosal epithelial barrier. But when the permeability of the epithelial barrier is elevated, digestive enzymes enter into the wall of the intestine and digest the intestinal tissue. The digestive enzymes may leak into the central circulation, and generate highly inflammatory mediators, including unbound free fatty acids and protein fragments. Once digestive enzymes and these inflammatory mediators are transported into the central circulation, cell dysfunctions and multiorgan dysfunction is encountered. Blockade of digestive enzymes with pancreatic protease and lipase inhibitors in the lumen of the intestine in acute forms of intestinal ischemia serves to reduce morphological damage to the mucosal barrier, preserves its permeability barrier properties, and attenuates the inflammation in the circulation. These results suggest that digestive enzymes in the lumen of the intestine play a central role in acute ischemia with symptoms of cell dysfunction and multiorgan failure.

Furthermore, our recent evidence suggests that a milder form of enzymatic degradation in the circulation also plays a central role in chronic conditions, such as insulin resistance (Type II Diabetes). Degrading enzymes cleave the extracellular domain of the insulin receptor, and therefore insulin lacks its binding site and the ability to signal glucose transport into the cell. The enzymatic destruction of the insulin receptors is observed in multiple models of Type II Diabetes and can be attenuated by chronic blockade of the degrading enzymes in the circulation.

This Event is For: Graduate • Faculty • Post-Docs

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