Pancreatic enzymes sustain systemic inflammation after an initial endotoxin challenge.
BACKGROUND
Sepsis is accompanied by severe inflammation whose mechanism remains uncertain. We recently demonstrated that pancreatic proteases in the ischemic intestine have the ability to generate powerful inflammatory mediators that can be detected in the portal vein and in the general circulation. This study was designed to examine several circulatory and inflammatory indices during experimental endotoxemia and intraintestinal pancreatic protease inhibition.


METHODS
Immediately after intravenous endotoxin administration, the small intestine was subjected to intraluminal lavage with and without gabexate mesilate, an inhibitor of pancreatic proteases. Shams and rats without lavage served as controls. Hemodynamics, leukocyte (neutrophil and monocyte), and endothelial cell activation, as well as organ injury in the intestine and the cremaster muscle, were examined.


RESULTS
After endotoxin administration, control rats developed hypotension, tachycardia, hyperventilation, and leukopenia. The intestine and plasma contained mediators that activated leukocytes. The leukocyte-endothelial interaction within the cremaster muscle microcirculation was enhanced. Endotoxin administration resulted in elevated interleukin-6 plasma levels. Histologic evidence indicated liver and intestinal injury. In contrast, blockade of pancreatic proteases in the intestinal lumen significantly improved hemodynamic parameters and reduced all indices of inflammation in plasma and cell injury in skeletal muscle microcirculation.


CONCLUSIONS
Inflammatory mediators derived from the intestine by pancreatic proteases may be involved in the prolonged inflammatory response and sustain symptoms of sepsis after endotoxin challenge.
Fitzal
Florian
F
Department of Surgery, University of Vienna Medical School, Vienna, Austria.
Delano
Frank A
FA
Young
Corey
C
Rosario
Henrique S
HS
Junger
Wolfgang G
WG
Schmid-Schönbein
Geert W
GW
D000818:Animals; D010450:Endopeptidases / Q000502:physiology*; D004731:Endotoxins / Q000633:toxicity*; D006439:Hemodynamics; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D008297:Male; D010179:Pancreas / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D018746:Systemic Inflammatory Response Syndrome / Q000201:enzymology / Q000209:etiology*
D004731:Endotoxins; D015850:Interleukin-6; D010450:Endopeptidases