Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock.
Shock, sepsis, and multiorgan failure are associated with inflammation, morbidity, and high mortality. The underlying pathophysiological mechanism is unknown, but evidence suggests that pancreatic enzymes in the intestinal lumen autodigest the intestine and generate systemic inflammation. Blocking these enzymes in the intestine reduces inflammation and multiorgan dysfunction. We investigated whether enzymatic blockade also reduces mortality after shock. Three rat shock models were used here: hemorrhagic shock, peritonitis shock induced by placement of cecal material into the peritoneum, and endotoxin shock. One hour after initiation of hemorrhagic, peritonitis, or endotoxin shock, animals were administered one of three different pancreatic enzyme inhibitors--6-amidino-2-naphtyl p-guanidinobenzoate dimethanesulfate, tranexamic acid, or aprotinin--into the lumen of the small intestine. In all forms of shock, blockade of digestive proteases with protease inhibitor attenuated entry of digestive enzymes into the wall of the intestine and subsequent autodigestion and morphological damage to the intestine, lung, and heart. Animals treated with protease inhibitors also survived in larger numbers than untreated controls over a period of 12 weeks. Surviving animals recovered completely and returned to normal weight within 14 days after shock. The results suggest that the active and concentrated digestive enzymes in the lumen of the intestine play a central role in shock and multiorgan failure, which can be treated with protease inhibitors that are currently available for use in the clinic.
Department of Bioengineering, The Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Frank A
FA
DeLano
David B
DB
Hoyt
Geert W
GW
Schmid-Schönbein
D000818:Animals; D004063:Digestion / Q000187:drug effects; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007422:Intestines / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009928:Organ Specificity / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology*; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D057057:Serine Proteases / Q000378:metabolism*; D012769:Shock / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology*; D016019:Survival Analysis; D014336:Troponin / Q000097:blood
D011480:Protease Inhibitors; D014336:Troponin; D057057:Serine Proteases