Protease inhibition in the intestinal lumen: attenuation of systemic inflammation and early indicators of multiple organ failure in shock.
Our recent evidence suggests that pancreatic digestive enzymes in the lumen of the intestine may play a major role in the production of cardiovascular stimulatory factors during splachnic artery occlusion and reperfusion. These stimulators are detected in plasma, but their origin and mechanism of production has remained uncertain. We examine here in the rat the role of pancreatic enzymes with and without administration of a serine protease inhibitor (FOY) into the lumen of the small intestine during splanchnic artery occlusion (90 min) and reperfusion (120 min). In the presence of pancreatic enzyme inhibition in the lumen of the intestine, there is significantly enhanced survival rate, lower levels of inflammatory mediator production, the femoral artery blood pressure is maintained close to control levels, and there are significantly lower levels of cell activators in plasma. These results support the hypothesis that pancreatic enzymes may escape across the brush border barrier during intestinal ischemia and thereby initiate the production of a powerful set of cytotoxic mediators. Blockade of pancreatic enzymes in the lumen of the intestine may be a tool to interfere with inflammation and early indicators of multiorgan failure.
Mitsuoka
Hiroshi
H
Department of Bioengineering, The Whitaker Institute for Biomedical Engineering, University of California, La Jolla 92093-0412, USA.
Kistler
Erik B
EB
Schmid-Schönbein
Geert W
GW
D000818:Animals; D001794:Blood Pressure; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives / Q000494:pharmacology; D006146:Guanidines; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000503:physiopathology; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000503:physiopathology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009503:Neutropenia / Q000503:physiopathology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012769:Shock / Q000139:chemically induced / Q000503:physiopathology*; D013152:Splanchnic Circulation; D015996:Survival Rate
D004952:Esters; D006146:Guanidines; D010972:Platelet Activating Factor; D015842:Serine Proteinase Inhibitors; C034532:camostat; D016670:Gabexate; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042932:formylmethionyl-leucyl-phenylalanine methyl ester; D010741:Phospholipases A; D010450:Endopeptidases; D012697:Serine Endopeptidases