LY255283, A NOVEL LEUKOTRIENE-B4 RECEPTOR ANTAGONIST, LIMITS ACTIVATION OF NEUTROPHILS AND PREVENTS ACUTE LUNG INJURY-INDUCED BY ENDOTOXIN IN PIGS

Background. Polymorphonuclear neutrophils (PMNs) have been implicated in the pathogenesis of the adult respiratory distress syndrome (ARDS). Because leukotriene B4 (LTB4) is a potent activator of PMNs, we sough t to determine whether LY255283, an LTB4 receptor antagonist, could bl ock PMN activation and lung injury in a porcine model of lipopolysacch aride-induced ARDS. Methods. Eighteen hours before being studied, pigs were injected with lipopolysaccharide (20 mug/kg). From 0 to 60 minut es, pigs received either Ringer's lactate solution (n = 5) or lipopoly saccharide (250 mug/kg). Among the pigs that were infused with lipopol ysaccharide, nine received no other treatment, six received a low dose of LY255283 (30 mg/kg loading dose; 3 mg/kg-hr infusion), and six rec eived a high dose of LY255283 (30 mg/kg loading dose, 30 mg/kg-hr). In vivo PMN activation was assessed with an automated chemiluminescence assay wherein results are expressed as CORE/MORE (i.e., the ratio of c omplement-opsonized zymosan receptor expression on circulating cells  CORE! divided by the maximal complement-opsonized zymosan receptor exp ression induced by incubating the cells in vitro with LTB4 or platelet -activating factor MORE!). Results. In control pigs, lipopolysacchari de induced hypoxemia, pulmonary hypertension, and neutrophil activatio n (increased CORE/MORE ratio). These changes were attenuated by LY2552 83, particularly when pigs were infused with the higher dose of the co mpound. The drug also blunted lipopolysaccharide-induced recruitment o f PMNs in pulmonary air spaces, as assessed by bronchoalveolar lavage performed at 240 minutes, although the degree of pulmonary leukoseques tration caused by lipopolysaccharide was not affected. Conclusions. In a dose-dependent fashion, LY255283 ameliorated lipopolysaccharide-ind uced ARDS in pigs, possibly by blocking the recruitment of activated P MNs into alveoli.