UC San Diego

Following reduced blood flow or trauma (e.g. in a car accident, explosion, burn, major surgery) a cascade of reactions leads to Shock and subsequently multi-organ failure (MOF) even if the organs were not affected by the initial trauma. Identifying the root cause of shock is of extraordinary importance and one of the greatest challenges for Bioengineering analysis. Shock is associated with one of the highest levels of mortality and no effective medical treatment exists. We have obtained evidence that pancreatic digestive enzymes are key players and we hypothesize that the intestinal mucosal/epithelial layer provides a physical barrier that prevents the entry of digestive enzymes, normally contained within the lumen of the intestine, and during ischemic states this layer becomes disrupted allowing access of these enzymes into the intestinal wall. The rationale for the proposed study is to provide an enhanced understanding of fundamental mechanisms in the degradation of the mucosal epithelial barrier and subsequent transport of digestive enzymes. In this study I propose to investigate during early stages of intestinal ischemia the transport and activity of digestive enzymes across the epithelial wall and determine changes in the mucosal epithelial barrier. I will investigate mechanisms leading to the disruption of the mucosal barrier using a rat model of splanchnic ischemia as well as non-ischemic models designed to understand whether events characteristic of ischemia, such hypoxia, ATP depletion or drop in pH, are responsible for the disruption of the mucosal/epithelial barrier. Furthermore, I will investigate alterations in intestinal permeability in order to understand the mechanism by which digestive enzymes or any other cytotoxic mediators are transported into the systemic circulation. The results of these studies will determine the role of the mucosal epithelial barrier in the transport of digestive enzymes into the intestinal wall and it will provide insight into the development of new treatments for shock