The prophylactic effects of selectin inhibitors on lipopolysaccharide-induced acute lung injury were studied in rabbits by using sialyl Lewis X-oligosaccharide and PB1.3, an anti-human P-selectin monoclonal antibody. Lipopolysaccharide-induced acute lung injury resembles that of the acute respiratory distress syndrome, in which there is a decrease in arterial blood oxygen tension (PaO2) and an increase in the difference between alveolar and arterial oxygen tension (A-aDO2). Prophylactic treatment with the selectin inhibitors, sialyl Lewis X-oligosaccharide (55 mg kg(-1) i.v. bolus injection immediately before lipopolysaccharide administration + 36 mg kg(-1) h(-1) i.v. infusion for 4 h) and PB1.3 (5 mg kg(-1) i.v. bolus injection immediately before lipopolysaccharide administration), prevented the lipopolysaccharide-induced impairments in pulmonary gas exchange. In contrast, these agents had no significant effects on lipopolysaccharide-induced systemic hypotension, the decrease in the number of circulating white blood cells and platelets, the decline in blood pH, or the increase in arterial CO2 tension (PaCO2). These results indicate that selectin inhibitors including sialyl Lewis X-oligosaccharide and the anti-P-selectin antibody, PB1.3, attenuate lipopolysaccharide-induced acute lung injury in rabbits. This is the first demonstration that P-selectin is directly involved in the development of lipopolysaccharide-induced impairments in pulmonary gas exchange.