title: Cytokine and radical inhibition in septic intestinal barrier failure.
abstract: BACKGROUND
  Breakdown of the intestinal barrier is a driving force of sepsis and multiple organ failure. Radical scavengers or cytokine inhibitors may have a therapeutic impact on intestinal failure. Therapeutic effects on different sites of small intestine and colon have not been compared. Therefore, we investigated time-dependent intestinal permeability changes and their therapeutic inhibition in colon and small intestine with an ex vivo model.
  
  
  METHODS
  Male Sprague-Dawley rats were either pretreated for 24 h with lipopolysaccharide (LPS) intraperitoneally alone or in combination with a radical scavenger (pyruvate or Tempol) or a cytokine inhibitor (parecoxib or vasoactive intestinal peptide). The gastrointestinal permeability was measured by time-dependent fluorescein isothiocyanate inulin diffusion using washed and everted tube-like gut segments. Blood and tissue samples were taken to investigate the development of inflammatory cytokine level (interleukin 6) in the context of cytokine inhibition and reactive oxygen species level via nicotinamide adenine dinucleotide phosphate oxidase activity in radical scavenger groups.
  
  
  RESULTS
  After LPS treatment, mucosal permeability was enhanced up to 170% in small intestine and colon. In the small intestine the most significant reduction in permeability was found for pyruvate and parecoxib. Treatment with vasoactive intestinal peptide and parecoxib resulted in the most pronounced reduction of permeability in the colon.
  
  
  CONCLUSIONS
  Our data suggest that cytokine inhibitors and radical scavengers have pronounced effects in LPS-induced disrupted intestinal barrier of the colon and small intestine. Our novel model comparing different anatomic sites and different points in time after the onset of sepsis may contribute to gain new insight into mechanisms and treatment options of sepsis-related gut mucosal breakdown.
authors.affiliation: Department of General and Visceral Surgery, Albert-Ludwigs-University of Freiburg, Freiburg, Germany. Electronic address: konrad.schulz@uniklinik-freiburg.de.
authors.forename: Konrad
authors.initials: K
authors.lastname: Schulz
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Sommer
authors.affiliation: Department of General and Visceral Surgery, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jargon
authors.affiliation: Department of General and Visceral Surgery, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Utzolino
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Clement
authors.affiliation: Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek St. Adolf-Stift, Reinbek, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Strate
authors.affiliation: Department of General and Visceral Surgery, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; Department of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek St. Adolf-Stift, Reinbek, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: von Dobschuetz
mesh_terms: D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood; D007413:Intestinal Mucosa / Q000187:drug effects*; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D008070:Lipopolysaccharides; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control*; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology; D010539:Permeability / Q000187:drug effects; D019289:Pyruvic Acid / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications; D013113:Spin Labels; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D003497:Cyclic N-Oxides; D052246:Cyclooxygenase 2 Inhibitors; D016166:Free Radical Scavengers; D015850:Interleukin-6; D007555:Isoxazoles; D008070:Lipopolysaccharides; D013113:Spin Labels; D014660:Vasoactive Intestinal Peptide; D019289:Pyruvic Acid; C409945:parecoxib; D019255:NADPH Oxidases; C001803:tempol
keywords: Colon; Gut; LPS; Permeability; Pyruvate; Rat; Sepsis; Small intestine; Tempol; VIP