ACUTE LUNG INJURY IN ENDOTOXEMIC PIGS - ROLE OF LEUKOTRIENE B-4

The role of leukotriene B-4 (LTB(4)) in the pathogenesis of acute lung injury was examined in endotoxemic pigs. In a preliminary study, the activity and specificity of an LTB(4)-receptor antagonist, LY-306669, were evaluated. In vitro, LY-306669 completely blocked the functional upregulation of phagocyte opsonin receptors induced by LTB(4) but had a much smaller effect on opsonin receptor upregulation induced by plat elet-activating factor. In pigs, treatment with LY-306669 prevented le ukopenia induced by injection of authentic LTB(4) but had no effect on the hematologic or hemodynamic effects of PAF or U-48816, a thromboxa ne-A(2) mimetic. In a second study, pigs received an intravenous primi ng dose of lipopolysaccharide (LPS) at time (t) = -18 h and were rando mized to receive 1) no further treatment (n = 5), 2) LPS (250 mu g/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 ameliorate d LPS-induced hypoxemia, pulmonary edema, and alveolitis. These data s uggest that LTB(4) is an important mediator of pulmonary dysfunction a nd transendothelial migration of neutrophils in LPS-induced acute lung injury.