title: Amelioration of endotoxin-induced sepsis in rats by membrane anchored lipid conjugates.
abstract: OBJECTIVE
  In the pathogenesis of septic shock, caused by either bacterial toxins or trauma, increased production of multiple proinflammatory mediators, such as phospholipase A(2) (PLA(2)), cytokines, and chemokines, is known to be of major importance. The present study was undertaken to investigate the influence of a newly designed extracellular PLA(2) inhibitor (ExPLI) on synthesis of proinflammatory mediators and mortality rate in a rat sepsis model.
  
  
  METHODS
  Prospective, randomized animal study.
  
  
  METHODS
  Experimental laboratory.
  
  
  METHODS
  Male Wistar-rats weighing 200-300 g.
  
  
  METHODS
  Mortality was induced by intraperitoneal bolus administration of lipopolysaccharide 15 mg/kg in 22 rats that were pretreated with NaCl or ExPLI (150 mg/kg). Furthermore, nine rats received a sublethal bolus of lipopolysaccharide (7.5 mg/kg) and nine rats received lipotechoic acid (8 mg/kg) simultaneously with or after ExPLI administration. Blood samples were collected from these rats, and cytokine concentrations were assessed by enzyme-linked immunosorbent assay. Lung and kidney were removed for RNA isolation and immunohistological analysis.
  
  
  RESULTS
  ExPLI treatment significantly reduced lipopolysaccharide-induced mortality of rats (90.9 and 36.4%, p <.05). Up-regulation of tumor necrosis factor-alpha and interleukin-6 production in serum after endotoxin treatment was significantly inhibited when ExPLIs were administered at the time of or before sepsis induction by using lipopolysaccharide or lipotechoic acid (p <.01). Similarly, messenger RNA expression of secreted PLA(2)-IIA, interleukin-1, or inducible nitric oxide synthase and the expression of intercellular adhesion molecule-1 were significantly down-regulated in lung and kidney of ExPLI-treated rats, as demonstrated by RNase protection assay, reverse transcription-polymerase chain reaction, or immunohistochemistry.
  
  
  CONCLUSIONS
  ExPLIs may be considered as potentially effective compounds to prevent the production of inflammatory mediators and to improve mortality rate in septic patients.
authors.affiliation: Insitute of Aneasthesiology, University of Mannheim, Germany. grietje.beck@anaes.ma.uni-heidelberg.de
authors.forename: Grietje Ch
authors.initials: GCh
authors.lastname: Beck
authors.forename: Wilhelm C
authors.initials: WC
authors.lastname: Hermes
authors.forename: Benito A
authors.initials: BA
authors.lastname: Yard
authors.forename: Marietta
authors.initials: M
authors.lastname: Kaszkin
authors.forename: Detlef
authors.initials: D
authors.lastname: von Zabern
authors.forename: Jutta
authors.initials: J
authors.lastname: Schulte
authors.forename: Markus
authors.initials: M
authors.lastname: Haak
authors.forename: Katharina
authors.initials: K
authors.lastname: Prem
authors.forename: W
authors.initials: W
authors.lastname: Krimsky
authors.forename: Klaus
authors.initials: K
authors.lastname: van Ackern
authors.forename: Fokko J
authors.initials: FJ
authors.lastname: van der Woude
authors.forename: Saul
authors.initials: S
authors.lastname: Yedgar
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood*; D004337:Drug Carriers; D018836:Inflammation Mediators / Q000097:blood*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D008563:Membrane Lipids; D010741:Phospholipases A / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000276:immunology* / Q000473:pathology
chemical_list: D001798:Blood Proteins; D016207:Cytokines; D004337:Drug Carriers; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008563:Membrane Lipids; C400481:PLIalpha; D018799:Intercellular Adhesion Molecule-1; D010741:Phospholipases A