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Bactericidal and endotoxin neutralizing activity of a peptide derived fromLimulusantilipopolysaccharide factor

Authors
Journal
Surgery
0039-6060
Publisher
Elsevier
Volume
128
Issue
2
Identifiers
DOI: 10.1067/msy.2000.108061
Disciplines
  • Biology
  • Medicine

Abstract

Abstract Background: Release of lipopolysaccharide (endotoxin, LPS) is a critical inciting event in the development of sepsis syndrome due to gram-negative bacteria, and mortality associated with this entity remains ~40%. Limulus anti-LPS factor (LALF) is a naturally occurring horseshoe crab derived protein that, unlike antibiotics, is both bactericidal for gram-negative bacteria and capable of neutralizing LPS. We hypothesized that a peptide derived from the active domain of LALF (LALF #28-54) would exhibit potent biologic activity similar to that of LALF itself and could potentially be useful as a therapeutic agent. Methods: The effects of LALF, synthetic peptide LALF #28-54, polymyxin B (PmB), and a biologically inactive synthetic peptide were examined in several models. In vitro bactericidal activity was determined against Pseudomonas aeruginosa, and LPS-neutralizing capacity was determined via inhibition of LPS-induced tumor necrosis factor–α (TNF-α) secretion by RAW 264.7 cells. In vivo biologic activity was determined via pretreatment following which P aeruginosa endotoxemia or bacteremia was induced; serum TNF-α levels, bacterial clearance, and survival were assessed. Results: LALF and LALF #28–54 exhibited potent in vitro bactericidal and LPS-neutralizing activity comparable to PmB (P <.01). However, although LALF #28-54 diminished systemic TNF-α production and aided bacterial clearance similar to that observed for LALF (P <.01), it did not provide significant protective capacity (P >.1). Conclusions: These data demonstrate that peptide LALF #28-54 retained the LPS-neutralizing and bactericidal biologic activity of LALF but failed to protect during overwhelming P aeruginosa bacteremia, perhaps due to short serum half-life.(Surgery 2000;128:339-44.)

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