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.
Suematsu
M
M
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Miura
S
S
Suzuki
M
M
Nagata
H
H
Morishita
T
T
Oshio
C
C
Tsuchiya
M
M
D000165:Acridine Orange / Q000494:pharmacology; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016227:Benzoquinones; D001794:Blood Pressure; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism*; D004731:Endotoxins / Q000008:administration & dosage / Q000009:adverse effects*; D005609:Free Radicals; D007262:Infusions, Intravenous; D016859:Lipoxygenase Inhibitors; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010100:Oxygen; D011809:Quinones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014680:Veins
D016227:Benzoquinones; D004731:Endotoxins; D005609:Free Radicals; D016859:Lipoxygenase Inhibitors; D011809:Quinones; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001091:Arachidonate Lipoxygenases; D000165:Acridine Orange; D010100:Oxygen