UC San Diego

Circulatory shock is a frequent cause of death and one of the most important unresolved medical problems. Reduction of blood supply to the small intestine during ischemia disrupts the mucosal epithelial barrier, allowing inflammatory materials in the lumen of the intestine, including digestive enzymes, to cross into the intestinal wall. If digestive enzymes are transported into the periphery, they can activate other proteases and degrade extracellular structures. Understanding the contribution of degrading proteases to circulatory shock may be essential to interfere with its lethal course. My objective is to determine which proteases are involved in the progression of shock and their contribution to intestinal degradation and peripheral organ failure. I hypothesize that during shock, the intestine is proteolytically degraded, accelerating leakage of proteases into the plasma, lymphatics, and peritoneal space, which may cause subsequent activation of proteases in peripheral organs and degradation of extracellular structures on endothelial and epithelial cells. To determine degradative mechanisms inherent to the intestinal wall and independent of luminal contents, I will use a model of severe intestinal ischemia to study barrier failure, digestive and wall proteases, and epithelial protein degradation. I will study the activities and transport of digestive proteases from the lumen of the intestine during hemorrhagic shock. I will determine the contribution of luminal contents to intestine and lung injury after hemorrhagic shock. Lastly, I will test methods to prevent breakdown of the intestinal barrier to reduce penetration of luminal contents past the mucosal barrier and reduce peripheral organ injury. I obtained evidence that the intestinal tissue degrades in severe ischemia even without luminal digestive enzymes. In hemorrhagic shock, I show that luminal contents are responsible for intestinal injury but not lung injury as determined by neutrophil accumulation and endothelial protein degradation. Protease activity and levels are elevated in the peritoneal space, lymph, blood, and vital organs after hemorrhagic shock. Protease inhibition to the gut reduces intestinal injury and protein degradation in the lung. These results suggest that proteases play a critical role in the pathophysiology of shock and may be important targets to reduce organ injury