Inhibitory effects of the peptide (CKPV)2 on endotoxin-induced host reactions

Stefano Gatti, Andrea Carlin, Andrea Sordi, Patrizia Leonardi, Gualtiero Colombo, Luigi R. Fassati, James M. Lipton, Anna Catania

Research output: Contribution to journalArticlepeer-review

Abstract

Background. α-Melanocyte stimulating hormone (α-MSH) is an endogenous peptide that has remarkable anti-inflammatory and antimicrobial effects. These activities have been traced to the C-terminal tripeptide Lys-Pro-Val (KPV). A dimer composed of two KPV sequences connected with a Cys-Cys linker, (CKPV)2, is currently under clinical investigation for antimicrobial use. The present research was designed to evaluate effects of (CKPV)2 on endotoxin-induced host reactions in vitro and in vivo. Materials and methods. Effects of (CKPV)2, KPV, and [Nle4-dPhe7]-α-MSH (NDP-α-MSH) on tumor necrosis factor α (TNF-α) production were determined: 1) in human peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) in vitro, and 2) in rats injected with LPS i.v. and sacrificed at 1 h. In additional experiments, dialysis peritonitis was induced in rats by adding LPS to dialysis fluid. Net ultrafiltrate was calculated and concentrations of nitrite (NO 2 -) and TNF-α were measured in blood and peritoneal fluid at 7 h. Results. (CKPV)2 inhibited TNF-α production by LPS-stimulated human PBMC. This small peptide was as effective as NDP-α-MSH and more potent than KPV. Similar effectiveness was observed in vivo: 1 h after LPS injection, the large increase in circulating TNF-α was markedly reduced by (CKPV)2 treatment. In LPS-induced peritonitis, (CKPV)2 restored net ultrafiltrate to control values and significantly inhibited concentrations of TNF-α and NO2 - both in plasma and in dialysate. Conclusions. The remarkable capacity of (CKPV)2 to inhibit endotoxin-induced host reactions suggests that it may be useful in treatment of inflammatory disorders.

Original languageEnglish
Pages (from-to)209-214
Number of pages6
JournalJournal of Surgical Research
Volume131
Issue number2
DOIs
Publication statusPublished - Apr 2006

Keywords

  • α-Melanocyte stimulating hormone (α-MSH)
  • Endotoxin
  • Nitric oxide (NO)
  • Peritoneal dialysis
  • Peritonitis
  • Synthetic melanocortins
  • Tumor necrosis factor α (TNF-α)

ASJC Scopus subject areas

  • Surgery

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