A NOVEL LEUKOTRIENE B-4-RECEPTOR ANTAGONIST IN ENDOTOXIN-SHOCK - A PROSPECTIVE, CONTROLLED TRIAL IN A PORCINE MODEL

Objective: To evaluate the hypothesis that treatment with LY255283, a novel leukotriene B, receptor antagonist, is beneficial in an animal model of the adult respiratory distress syndrome induced by endotoxin. Design: Prospective, randomized, controlled trial. Setting: Laboratory at a large university medical center. Subjects: Twenty-five, immature. random-bred swine. Interventions: Four groups of pigs were studied: the LPS group of animals (n = 6) were infused with Escherichia coli lipopolysaccharide (strain 0111:B4, 250 mu g/kg) from 0 to 60 mins; the LPS + 255283 group of animals (n = 6) were infused with lipopolysaccharide as above, but were also treated with LY255283 (30 mg/kg, then 10 mg/kg/hr), beginning at -15 mins; the 255283 group, of animals (n = 6) were infused with the same dose of LY255283, but were not challenged with lipopolysaccharide; and the RL control group of subjects (n = 7) received only the lactated Ringer's solution vehicle. Beginning at 30 mins, all groups were infused with dextran-70 solution as needed to maintain cardiac output at 90% to 110% of baseline value. Measurements and Main Results: Treatment with LY255283 significantly (p < .05) ameliorated lipopolysaccharide-induced systemic arterial hypotension, pulmonary arterial hypertension, and arterial hypoxemia. Treatment with this drug also abrogated Lipopolysaccharide-induced increases in pulmonary extravascular water content and bronchoalveolar lavage fluid protein concentration. Conclusions: These data suggest that leukotriene B-4 may be an important mediator of acute lung injury in this porcine model of septic shock and acute lung injury. Further studies to assess the specificity of LY255283 as a leukotriene B-4 antagonist are necessary in order to exclude the possibility that the beneficial effects of this compound are due to pharmacologic actions other than the blockade of LTB(4) receptors.