Pancreatic protease inhibition during shock attenuates cell activation and peripheral inflammation

Intestinal ischemia contributes to shock-induced multiple organ failure. Our recent evidence suggests that pancreatic proteases may be involved in the formation of inflammatory activators within an ischemic intestine. These inflammatory mediators are released early into the circulation and may contribute to the severe systemic inflammatory response syndrome (SIRS) during shock. We examined the impact of intra-intestinal pancreatic protease inhibition on acute intestinal ischemia-induced hypotension, the formation of activating factors for cardiovascular cells, as well as cremaster muscle cell death and intestinal injury by intravital microscopy. Male Wistar rats were divided into four groups: (1) a sham group; and experimental groups with 100 min of superior mesenteric artery occlusion (2) without (SMAO group), and (3) with intestinal lavage using Krebs-Henseleit solution (LAV group), or (4) lavage using the protease inhibitor gabexate mesilate in Krebs-Henseleit solution (FOY group, 0.37 mM). Intestinal ischemia and reperfusion-induced hypotension upon reperfusion was accompanied by a significant increase in the level of neutrophil-activating factors in the intestine and plasma. During reperfusion, a significant increase in leukocyte-endothelium interactions in postcapillary venules and parenchymal cell death were observed in the cremaster muscle in LAV and SMAO animals suggesting peripheral neutrophil cell activation. Intra-intestinal pancreatic protease inhibition resulted in a stable blood pressure throughout the experiment. Cell activation, leukocyte-endothelial interactions and cell death in the cremaster muscle were almost completely abolished in the FOY group. In addition, ischemia-induced intestinal mucosal injury was attenuated with intestinal pancreatic protease inhibition. These results indicate that intestinal pancreatic protease inhibition significantly attenuates intestinal ischemia-induced shock by reducing SIRS and gut injury.