Protease Inhibition to Optimize the Intestinal Mucosal Barrier to Digestive Enzymes during Hemorrhagic Shock

Abstract

Our recent evidence indicates that escape of pancreatic digestive enzymes from the lumen into the wall of the intestine after breakdown of the mucosal barrier causes autodigestion and multiorgan failure in hemorrhagic shock. We hypothesize that initial opening of the mucosal barrier in the small intestine is mediated by matrix‐metallo proteinases (MMPs). We determined the level of pancreatic trypsin leakage into the intestine by immunohistochemistry of intestinal sections after hemorrhagic shock (35 mmHg mean arterial pressure for 2 hours). Two forms of protease inhibition were studied, single enteral inhibition with a MMP inhibitor (doxycycline, 5 mg/kg, i.v.) without and with enteral serine protease inhibition (127 mM tranexamic acid in 17 ml distributed uniformly over the small intestine of a 300 gm rat by local injections). As shown previously, the enteral inhibition of protease activity with tranexamic acid served to reduce the entry of pancreatic trypsin (detected with a mAb) across the mucosal barrier into the villi and mucosal tissue. Dual blockade with the MMP inhibitor (i.v.) and enteral serine protease inhibitor reduced the level of pancreatic trypsin in the intestinal wall to a level that was not significantly different from non‐shock controls. We detected a similar level of protection against entry of pancreatic amylase into the wall of the intestine by the combined enteral and i.v. protease inhibition. These results indicate that the irreversible opening of the mucosal barrier in hemorrhagic shock involves multiple proteases and a dual inhibition serves to minimize the leakage of digestive enzymes out of the lumen of the small intestine. The dual blockade of proteases may have clinical utility in shock patients.Support or Funding InformationSupported by GM 85072