Generation of in vivo activating factors in the ischemic intestine by pancreatic enzymes

One of the early events in physiological shock is the generation of activat ors for leukocytes, endothelial cells, and other cells in the cardiovascula r system. The mechanism by which these activators are produced has remained unresolved. We examine here the hypothesis that pancreatic digestive enzym es in the ischemic intestine may be involved in the generation of activator s during intestinal ischemia. The lumen of the small intestine of rats was continuously perfused with saline containing a broadly acting pancreatic en zyme inhibitor (6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfate, 0.37 mM) before and during ischemia of the small intestine by splanchnic ar tery occlusion. This procedure inhibited activation of circulating leukocyt es during occlusion and reperfusion, It also prevented the appearance of ac tivators in portal venous and systemic artery plasma and attenuated initiat ing symptoms of multiple organ injury in shock. Intestinal tissue produces only low levels of activators in the absence of pancreatic enzymes, whereas in the presence of enzymes, activators are produced in a concentration- an d time-dependent fashion. The results indicate that pancreatic digestive en zymes in the ischemic intestine serve as an important source for cell activ ation and inflammation, as well as multiple organ failure.