Effect of a 5-lipoxygenase inhibitor on endotoxin-induced pulmonary dysfunction in awake sheep.
We studied the effects of a 5-lipoxygenase inhibitor, SC-45662, on endotoxin-induced pulmonary dysfunction in chronically instrumented unanesthetized sheep. Each sheep was studied with endotoxin alone, SC-45662 alone, and endotoxin after SC-45662 pretreatment. Endotoxin did not cause consistent increases in plasma or lung lymph concentrations of leukotriene B4 (LTB4). Ex vivo stimulation of whole blood from sheep before and after treatment with SC-45662 demonstrated no inhibition of cyclooxygenase metabolism but an approximately 80% inhibition of LTB4 production. At drug concentrations obtained in vivo, SC-45662 did not significantly inhibit in vitro A23187-stimulated whole blood thromboxane B2 production but did inhibit LTB4 production from ionophore-stimulated sheep granulocytes. SC-45662 attenuated the early changes in lung mechanics and pulmonary hypertension but did not attenuate the later increase in lung fluid and solute exchange observed after endotoxemia. We conclude that 5-lipoxygenase products are not measurably involved in the later increase in lung fluid and solute exchange observed after endotoxemia in sheep.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Y
Y
Kuratomi
P L
PL
Lefferts
B W
BW
Christman
R E
RE
Parker
W G
WG
Smith
R A
RA
Mueller
J R
JR
Snapper
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000085:Acetates; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007975:Leukotriene B4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008208:Lymphatic System / Q000187:drug effects; D008297:Male; D010636:Phenols; D010640:Phenothiazines / Q000494:pharmacology; D015656:Respiratory Mechanics / Q000187:drug effects; D012756:Sheep; D013481:Superoxides / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism
D000085:Acetates; D004731:Endotoxins; D016859:Lipoxygenase Inhibitors; D010636:Phenols; D010640:Phenothiazines; D013481:Superoxides; C066992:(2-((3,5-di-t-butyl-4-hydroxyphenyl)thio)-1-methylpropoxy)acetic acid; D007975:Leukotriene B4; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C053726:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one; D001094:Arachidonate 5-Lipoxygenase; D015232:Dinoprostone