Administration of protegrin peptide IB-367 to prevent endotoxin induced mortality in bile duct ligated rats

Abstract

Background: Postoperative morbidity in patients with obstructive jaundice remains high because of increased susceptibility to endotoxin and the inflammatory cascade. Aims: An experimental study was designed to investigate the efficacy of protegrin peptide IB-367, an antimicrobial positively charged peptide, in neutralising Escherichia coli 0111:B4 lipopolysaccharide (LPS) in bile duct ligated rats. Methods: Adult male Wistar rats were injected intraperitoneally with 2 mg/kg E coli 0111:B4 LPS one week after sham operation or bile duct ligation (BDL). Six groups were studied: sham with placebo, sham with 120 mg/kg tazobactam-piperacillin (TZP), sham with 1 mg/kg IB-367, BDL with placebo, BDL with 120 mg/kg TZP, and BDL with 1 mg/kg IB-367. Results: Main outcome measures were: endotoxin and tumour necrosis factor α (TNF-α) concentrations in plasma, evidence of bacterial translocation in blood and peritoneum, and lethality. After LPS, TNF-α plasma levels were significantly higher in BDL rats compared with sham operated animals. IB-367 caused a significant reduction in plasma endotoxin and TNF-α concentrations compared with placebo and TZP treated groups. In contrast, both TZP and IB-367 significantly reduced bacterial growth compared with saline treatment. Finally, LPS induced 60% and 55% lethality in BDL placebo and TZP treated rats and no lethality in sham operated rats, while only IB-367 significantly reduced lethality to 10%. Conclusions: By virtue of its dual antimicrobial and antiendotoxin properties, IB-367 could be an interesting compound to inhibit bacterial translocation and endotoxin release in obstructive jaundice.