5-lipoxygenase inhibitor (AA-861) attenuates neutrophil-mediated oxidative stress on the venular endothelium in endotoxemia

J Clin Lab Immunol. 1988 Jan;25(1):41-5.

Abstract

Neutrophil-mediated oxidative stress on the rat mesenteric microcirculation was studied in the experimental model of endotoxin-induced disseminated intravascular coagulation (DIC) by using an intravital fluorescent microscope equipped with a Silicon Intensifier Target Image Tube camera and luminol-dependent chemiluminescence (ChL) analysis. Leukocytes adhering to the venules were visualized by the injection of acridine orange, a fluorochrome tracer which shows high affinity to white cells. Endotoxin (E. coli, O-111 B4) was administered intravenously at a dose of 2 mg/kg/hour. After starting the infusion of endotoxin, the number of adherent cells gradually increased in the venular endothelium and was followed by a transient neutropenia. ChL activities from neutrophils were also significantly elevated, which may reflect the enhanced ability to generate oxygen-radicals. To elucidate the role of 5-lipoxygenase products in the locomotive and metabolic changes of neutrophils, the effects of AA-861, a specific inhibitor of 5-lipoxygenase was tested. In addition prednisolone and indomethacin were evaluated. AA-861 and prednisolone reduced neutropenia, leukocyte adhesion to the venular walls and ChL activities from neutrophils. It was concluded that 5-lipoxygenase may modulate neutrophil-mediated oxidative stress on microvasculature in endotoxin-induced DIC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridine Orange / pharmacology
  • Animals
  • Arachidonate Lipoxygenases / antagonists & inhibitors*
  • Benzoquinones*
  • Blood Pressure
  • Cell Adhesion / drug effects
  • Endothelium, Vascular / metabolism*
  • Endotoxins / administration & dosage
  • Endotoxins / adverse effects*
  • Free Radicals
  • Infusions, Intravenous
  • Lipoxygenase Inhibitors*
  • Male
  • Neutrophils / drug effects
  • Neutrophils / enzymology
  • Neutrophils / metabolism*
  • Oxygen
  • Quinones / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Veins

Substances

  • Benzoquinones
  • Endotoxins
  • Free Radicals
  • Lipoxygenase Inhibitors
  • Quinones
  • 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone
  • Arachidonate Lipoxygenases
  • Acridine Orange
  • Oxygen