Shock is a common cause of morbidity and mortality in the intensive care unit, with a mortality of 30-100%. VA hospitals are particularly impacted, in part secondary to the advanced age and co-morbidities of many of the veterans. The mechanisms leading to shock and cardiovascular collapse are incompletely understood. Likewise, there is no treatment for the extremely high morbidity seen in survivors of shock. However, it is becoming increasingly clear that the gut, and particular the small bowel, may be the key to understanding this condition and its sequelae. We have recently developed a new hypothesis describing possible important mechanisms in shock with the discovery that pancreatic digestive enzymes in the bowel may play a major role. This finding has enabled exploration of a potentially new treatment by digestive enzyme inhibition. We have recent initial evidence that blockade of digestive enzymes in the intestinal lumen, but not the systemic circulation, may abolish mortality and morbidity normally seen in experimental models of circulatory shock. However, the mechanisms by which digestive enzyme inhibition in the gut lumen is protective are not known. My hypothesis is that the normally intact brush border epithelial barrier is breached in shock, allowing digestive enzymes access to interstitial tissue with resulting intestinal wall destruction, inflammation and breakdown of basic cell functions. Mucosal barrier compromised by ischemia, endotoxins, or other injury, leads to entry of digestive enzymes into the intestinal wall, auto-digestion of the intestine and generation of inflammatory mediators that circulate systemically. I have found in preliminary studies that low molecular weight products generated by digestive enzymes may induce inflammation and shock. My first Specific Aim proposes to identify a number of representative inflammatory peptides derived from digestive enzymes themselves and demonstrate their presence and importance in the gut and systemic circulation of animals in splanchnic arterial occlusion (SAO) shock. A key question in long-term survival in shock is the time required for reconstitution of mucosal epithelium to its normal low permeability state. No studies have addressed long-term survival or morbidity in shock associated with an ischemic intestine. Furthermore, no systematic survival studies exist with intestinal enzyme blockade in SAO shock. My second Specific aim will determine by enzyme blockade in the intestine the role of pancreatic digestive enzymes in the generation of inflammatory and cytotoxic mediators and in long-term survival and morbidity after SAO shock in rat and mouse experimental models. I will establish a window of treatment for rescue therapy after shock and explore the feasibility of oral pre-treatment as an approach to the development of clinical intervention in shock and high-risk surgical procedures. I will also explore the role of gut mucosal protease activated receptor-2 (PAR-2) as a specific mechanism that contributes to morbidity and mortality after shock. These results will generate fundamental new knowledge about the pathogenesis of shock. They will provide a new understanding for the role digestive enzymes play in initiating ischemic injury in the intestine and optimize treatment strategies to interfere with their activity in shock, leading to potential clinical applications to decrease morbidity and mortality in this condition.
Shock is a common cause of patient morbidity and death in VA intensive care units (ICUs). VA hospitals are particularly impacted because of the advanced age and co-morbidities of many of the veterans. Unfortunately, other than supportive care, treatment options are limited because the pathogenesis of shock is incompletely understood. Our previous studies suggest that the gut may be an initiator of irreversible shock and we recently developed a new hypothesis describing possible important mechanisms with the discovery that pancreatic digestive enzymes may play a major role in this condition. The goals of this project are to establish the pathways by which gut pancreatic enzymes are active in shock and in a pre-clinical model optimize bowel enzyme inhibition as an eventual treatment strategy for circulatory shock and for prophylactic use before high-risk surgical procedures in the VA.