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

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.