Eosinophil chemotaxis inhibited by 5-lipoxygenase blockade and leukotriene receptor antagonism

Am J Respir Crit Care Med. 1997 Apr;155(4):1398-403. doi: 10.1164/ajrccm.155.4.9105085.

Abstract

We studied the effects of the 5-lipoxygenase inhibition and sulfidopeptidyl leukotriene receptor antagonism on lumenal chemotaxis of eosinophils in 124 guinea pig tracheal explant preparations from 62 animals. Cell migration was assessed histologically and by differential cell count, and airway narrowing was measured by calibrated micrometry. Intralumenal instillation of the chemotaxin, formyl-met-leu-phe (FMLP) caused migration of 163,509 +/- 18,103 eosinophils/cm segment (eos/cm) versus 15,443 +/- 3,557 eos/cm for segments receiving vehicle only (p < 0.001). Coincubation of FMLP with zileuton, a selective inhibitor of 5-lipoxygenase, caused a concentration-related inhibition of eosinophil migration. At 10(-10) M zileuton, cell migration caused by FMLP was decreased by 57% and nearly complete reduction to 17,200 +/- 3,620 eos/cm resulted after 10(-6) M zileuton (p < 0.001 versus FMLP). Lumenal narrowing caused by FMLP (15.3 +/- 3.4%) was attenuated maximally to 1.15 +/- 2.51% after 10(-8) M zileuton (p < 0.02). In 36 preparations, concentration of leukotriene B4 (LTB4) was measured in treated tracheal perfusate. LTB4 secretion caused by FMLP was 6.4 +/- 0.48 pg/ml versus 3.32 +/- 0.89 pg/ml for buffer control at 5 min (p < 0.02) and was undetectable 120 min after activation with FMLP. Blockade of LTB4-receptor with the selective antagonist, LTB4 dimethyl amide, caused > 90% inhibition of eosinophil migration (p < 0.001). Comparable results were obtained with zafirlukast, an LTD4-receptor antagonist. Our data demonstrate that both LTB4 and LTD4 facilitate eosinophil migration from lamina propria to lumen caused by the chemotaxin, FMLP, and that LTB4-induced eosinophil migration is accompanied by initial lumenal secretion of LTB4.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Movement / drug effects
  • Chemotaxis, Leukocyte / drug effects*
  • Eosinophils / drug effects*
  • Guinea Pigs
  • Hydroxyurea / analogs & derivatives*
  • Hydroxyurea / pharmacology
  • Leukotriene Antagonists*
  • Leukotriene B4 / metabolism
  • Leukotriene B4 / physiology
  • Leukotriene D4 / physiology
  • Lipoxygenase Inhibitors* / pharmacology
  • Male
  • Membrane Proteins*
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Receptors, Leukotriene B4 / antagonists & inhibitors
  • Receptors, Leukotriene*
  • Tosyl Compounds / pharmacology*
  • Trachea / cytology
  • Trachea / drug effects

Substances

  • Leukotriene Antagonists
  • Lipoxygenase Inhibitors
  • Membrane Proteins
  • Receptors, Leukotriene
  • Receptors, Leukotriene B4
  • Tosyl Compounds
  • Leukotriene B4
  • N-Formylmethionine Leucyl-Phenylalanine
  • Leukotriene D4
  • cysteinyl leukotriene receptor 2
  • leukotriene D4 receptor
  • zileuton
  • Hydroxyurea
  • zafirlukast