Lexipafant inhibits platelet activating factor enhanced neutrophil functions

Jess D. Schwartz, Peter Shamamian, Eugene A. Grossi, Daniel S. Schwartz, Stuart G. Marcus, Federico Steiner, Chad E. Jacobs, Majid Tayyarah, Kenneth Eng, Stephen B. Colvin, Aubrey C. Galloway

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Platelet activating factor (PAF) enhances polymorphonuclear leukocyte (PMN) superoxide (·O2) production, CD11b expression, and elastase release, all essential components in the pathophysiology of multiple-organ failure. This study was designed to determine the effects of Lexipafant, a PAF receptor antagonist, on PAF-mediated PMN functions. PMNs from 10 healthy volunteers were isolated and pretreated with various concentrations of Lexipafant (0-100 μM). PMNs were then incubated for 5 min with 200 nM PAF for ·O2 detection or 2000 nM PAF for elastase measurement and activated with 1 μM N-formylmethionylleucylphenylalanine. The mean rate of ·O2 production was determined by a cytochrome c reduction assay (nmole ·O2/min/1.33 x 106 PMN ± SEM). Elastase release was measured by the cleavage of the synthetic elastase substrate Meo-Suc-Ala-Ala-Pro-Val-pNA (mean elastolytic activity ± SEM). In parallel experiments, PMNs were incubated with 200 nM PAF for 30 min following pre-treatment with Lexipafant and CD11b expression was determined by flow cytometry (mean fluorescence intensity ± SEM). Statistical analysis was performed using repeated-measures ANOVA (P < 0.05). Lexipafant inhibited PAF-enhanced PMN ·O2 generation, CD11b expression and elastase release in a dose dependent fashion. The IC50 of Lexipafant for ·O2 production, CD11b expression, and elastase release was 0.046, 0.285, and 0.05 μM, respectively. Lexipafant attenuated the PAF- mediated upregulation of PMN ·O2 production, CD11b expression, and elastase release in a dose dependent fashion. These data support the hypothesis that Lexipafant may reduce the severity of the inflammatory response to injury produced by PAF-enhanced activation of PMNs.

Original languageEnglish (US)
Pages (from-to)240-248
Number of pages9
JournalJournal of Surgical Research
Volume69
Issue number2
DOIs
StatePublished - May 1997
Externally publishedYes

ASJC Scopus subject areas

  • Surgery

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