Acute lung injury in endotoxemic pigs: role of leukotriene B4.
The role of leukotriene B4 (LTB4) in the pathogenesis of acute lung injury was examined in endotoxemic pigs. In a preliminary study, the activity and specificity of an LTB4-receptor antagonist, LY-306669, were evaluated. In vitro, LY-306669 completely blocked the functional upregulation of phagocyte opsonin receptors induced by LTB4 but had a much smaller effect on opsonin receptor upregulation induced by platelet-activating factor. In pigs treatment with LY-306669 prevented leukopenia induced by injection of authentic LTB4 but had no effect on the hematologic or hemodynamic effects of PAF or U-48816, a thromboxane-A2 mimetic. In a second study, pigs received an intravenous priming dose of lipopolysaccharide (LPS) at time (t) = -18 h and were randomized to receive 1) no further treatment (n = 5), 2) LPS (250 micrograms/kg over 1 h beginning at t = 0 h) and LY-306669 (10 mg/kg bolus and 3 mg.kg-1.h-1 infusion beginning at t = -15 min) (n = 7), or 3) LPS and vehicle (n = 6). Treatment with LY-306669 significantly ameliorated LPS-induced hypoxemia, pulmonary edema, and alveolitis. These data suggest that LTB4 is an important mediator of pulmonary dysfunction and transendothelial migration of neutrophils in LPS-induced acute lung injury.
VanderMeer
T J
TJ
Department of Surgery, Massachusetts General Hospital, Boston 02114, USA.
Menconi
M J
MJ
O'Sullivan
B P
BP
Larkin
V A
VA
Wang
H
H
Sofia
M
M
Fink
M P
MP
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D004731:Endotoxins / Q000097:blood*; D006439:Hemodynamics / Q000187:drug effects; D007975:Leukotriene B4 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008171:Lung Diseases / Q000209:etiology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010636:Phenols / Q000494:pharmacology; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood
D004731:Endotoxins; D008070:Lipopolysaccharides; D010636:Phenols; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; C084687:LY 306669; D007975:Leukotriene B4; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha