title: Pancreatic enzymes sustain systemic inflammation after an initial endotoxin challenge.
abstract: 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.
authors.affiliation: Department of Surgery, University of Vienna Medical School, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Fitzal
authors.forename: Frank A
authors.initials: FA
authors.lastname: Delano
authors.forename: Corey
authors.initials: C
authors.lastname: Young
authors.forename: Henrique S
authors.initials: HS
authors.lastname: Rosario
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
authors.forename: Geert W
authors.initials: GW
authors.lastname: Schmid-Schönbein
mesh_terms: 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*
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; D010450:Endopeptidases