TY - JOUR
T1 - Lexipafant inhibits platelet activating factor enhanced neutrophil functions
AU - Schwartz, Jess D.
AU - Shamamian, Peter
AU - Grossi, Eugene A.
AU - Schwartz, Daniel S.
AU - Marcus, Stuart G.
AU - Steiner, Federico
AU - Jacobs, Chad E.
AU - Tayyarah, Majid
AU - Eng, Kenneth
AU - Colvin, Stephen B.
AU - Galloway, Aubrey C.
PY - 1997/5
Y1 - 1997/5
N2 - 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.
AB - 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.
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U2 - 10.1006/jsre.1997.5008
DO - 10.1006/jsre.1997.5008
M3 - Article
C2 - 9224389
AN - SCOPUS:0031148312
SN - 0022-4804
VL - 69
SP - 240
EP - 248
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 2
ER -