Impaired Small-Bowel Barrier Integrity in the Presence of Lumenal Pancreatic Digestive Enzymes Leads to Circulatory Shock

Abstract

In bowel ischemia, impaired mucosal integrity may allow intestinal pancreatic enzyme products to become systemic and precipitate irreversible shock and death. This can be attenuated by pancreatic enzyme inhibition in the small bowel lumen. It is unresolved, however, whether ischemically-mediated mucosal disruption is the key event allowing pancreatic enzyme products systemic access, and whether intestinal digestive enzyme activity in concert with increased mucosal permeability leads to shock in the absence of ischemia. To test this possibility, the small intestinal lumen of non-ischemic rats was perfused for two hours with either digestive enzymes, a mucin disruption strategy (i.e., mucolytics) designed to increase mucosal permeability, or both, and animals were observed for shock. Digestive enzymes perfused included trypsin, chymotrypsin, elastase, amylase and lipase. Control (n=6) and experimental animals perfused with pancreatic enzymes only (n=6) or single enzymes (n=3 for each of the five enzyme groups) maintained stable hemodynamics. After mucin disruption using a combination of enteral N-acetylcysteine, atropine, and increased flow rates, rats (n=6) developed mild hypotension (p<0.001 compared to groups perfused with pancreatic enzymes only after 90 minutes) and increased intestinal permeability to intralumenally perfused FITC-dextrans-20kD (p<0.05) compared to control and enzyme-only groups, but there were no deaths. All animals perfused with both digestive enzymes and subjected to mucin disruption (n=6) developed hypotension and increased intestinal permeability (p<0.001 after 90 minutes). Pancreatic enzymes were measured in the intestinal wall of both groups subjected to mucin disruption, but not in the enzyme-only or control groups. Depletion of plasma protease inhibitors was found only in animals perfused with pancreatic enzymes plus mucin disruption, implicating increased permeability and intralumenal pancreatic enzyme egress in this group. These experiments demonstrate that increased bowel permeability via mucin disruption in the presence of pancreatic enzymes can induce shock and increase systemic protease activation in the absence of ischemia, implicating bowel mucin disruption as a key event in early ischemia. Digestive enzymes and their products, if allowed to penetrate the gut wall may trigger multiorgan failure and death.

The Intestinal Mucus Layer is a Critical Component of the Gut Barrier that is Damaged During Acute Pancreatitis

“…Thus, one advantage of the pancreatic duct ligation model is that it eliminates luminal pancreatic enzymes and serves as a proof-of-principle model testing the role of mucus disruption on pancreatitis-induced gut permeability changes. Our results also suggest that pancreatic proteases are not likely necessary for the initiation of the mucus changes observed in early acute pancreatitis, although their presence could potentiate damage to the oxidant-modified mucus layer (33). …”

“…This is in contrast to toxin-induced models of pancreatitis wherein pancreatic proteases are secreted into the gut lumen and morphologic evidence of gut injury is more pronounced (27, 29-31). The potentially toxic role of luminal pancreatic proteases is supported by studies showing that the ischemic or stressed gut is susceptible to autodigestion by luminal digestive enzymes if they come into direct contact with the epithelial barrier (10, 32, 33). Thus, the fact that the duct ligation model prevents pancreatic enzymes from reaching the gut lumen could help explain the lack of microscopic morphologic evidence of gut injury.…”

Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure

“…In these studies, the presence of luminal pancreatic proteases only led to increased gut morphological injury and increased permeability when the mucus layer was impaired. Recent work from Schmid-Schonbein's group has also demonstrated that the intestinal mucus layer serves to limit digestive enzymes from reaching the gut epithelial layer in both normal animals and in animals subjected to a gut ischemia-reperfusion insult (5,17). In conclusion, decreases in splanchnic blood flow resulting in a gut ischemia-reperfusion insult appear to be necessary components of gut injury and loss of barrier function after T/HS, as well as in other model systems associated with gut ischemia.…”

Autodigestion

“…with mucolytic N-acetylcysteine treatment) allows digestive enzymes to enter the intestinal wall, a process that is followed by severe damage to the intestinal mucosa (20) and may lead to death even in the absence of any other systemic challenge (19). …”