title: The anti-inflammatory effect of the synthetic antimicrobial peptide 19-2.5 in a murine sepsis model: a prospective randomized study.
abstract: BACKGROUND
  Increasing rates of multi-resistant bacteria are a major problem in the treatment of critically ill patients. Furthermore, conventional antibiotics lead to the release of bacterial derived membrane parts initiating pro-inflammatory cascades with potential harm to the patient. Antimicrobial peptides (AMP) may kill bacteria without releasing pro-inflammatory factors. Thus, we compared three newly developed synthetic anti-lipopolysaccharide peptides (SALPs) with a broader range of efficacy to suppress cytokine release in plasma and CD14 mRNA expression in organ tissue in a murine, polymicrobial sepsis model.
  
  
  METHODS
  A randomized, experimental trial was conducted in an animal research facility. Male NMRI mice (n = 90; 8- to 12-weeks old) were randomized to the following six groups: (i) sham operation and parenteral vehicle (NaCl 0.9%) administration (sham); (ii) cecal ligation and puncture (CLP) and vehicle infusion (sepsis-control), (iii) CLP and polymyxin B infusion (polyB), or (iv to vi) CLP and infusion of three different synthetic antimicrobial peptides Peptide 19-2.5 (Pep2.5), Peptide 19-4 (Pep4) or Peptide 19-8 (Pep8). All animals underwent arterial and venous catheterization for hemodynamic monitoring 48 hours prior to CLP or sham-operation. Physical appearance and behavior (activity), plasma cytokine levels, and CD14 mRNA expression in heart, lung, liver, spleen and kidney tissue were determined 24 hours after CLP or sham operation.
  
  
  RESULTS
  Only Pep2.5 significantly enhanced the activity after CLP, whereas none of the therapeutic regimens elevated the mean arterial pressure or heart rate. The strongly elevated IL-6, IL-10 and monocyte chemoattractant protein serum levels in septic animals were significantly reduced after Pep2.5 administration (P < 0.001, P < 0.001, and P < 0.001, respectively). Similarly, Pep2.5 significantly reduced the sepsis-induced CD14 mRNA expression in heart (P = 0.003), lung (P = 0.008), and spleen tissue (P = 0.009) but not in kidney and liver.
  
  
  CONCLUSIONS
  Structurally variable SALPs exhibit major differences in their anti-inflammatory effect in vivo. Continuous parenteral administration of Pep2.5 is able to reduce sepsis-induced cytokine release and tissue inflammation.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schuerholz
authors.forename: Sabine
authors.initials: S
authors.lastname: Doemming
authors.forename: Mathias
authors.initials: M
authors.lastname: Hornef
authors.forename: Lukas
authors.initials: L
authors.lastname: Martin
authors.forename: Tim-Philipp
authors.initials: TP
authors.lastname: Simon
authors.forename: Lena
authors.initials: L
authors.lastname: Heinbockel
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
authors.forename: Gernot
authors.initials: G
authors.lastname: Marx
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000235:genetics / Q000627:therapeutic use*; D011446:Prospective Studies; D011897:Random Allocation; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C050394:PCP4 protein, human