We have previously described a model of
acute lung injury in the mouse in which
intravenous administration of
lipopolysaccharide (LPS) results in a marked sequestration of neutrophils in the pulmonary microvasculature, although this by itself was not sufficient to induce injury. If the sequestered neutrophils were exposed to
zymosan, then a striking increase in pulmonary vascular permeability to
albumin was found, suggesting that sequestered neutrophils may produce one or more mediators capable of acting directly on the capillary endothelium. Because activated neutrophils are known to release
platelet-activating factor (PAF), we hypothesized that PAF produced locally within the pulmonary capillaries may be the mediator involved. Treatment of mice with the PAF antagonist UK-74,505 prior to administration of
zymosan alone or combined LPS and
zymosan resulted in a substantial attenuation of
lung injury, as measured by the accumulation of extravascular 125I-labeled
human serum albumin. UK-74,505 had no effect on neutrophil sequestration as measured by
myeloperoxidase activity in whole lung tissue and as assessed by light microscopy. Administration of UK-74,505 after LPS, but before
zymosan, was also effective at inhibiting
lung injury but again, neutrophil sequestration was unaffected. In contrast, UK-74,505 had no effect on
cobra venom factor-induced
lung injury and neutrophil sequestration. These data suggest that PAF production is involved in the increases in pulmonary vascular permeability, but not in the sequestration of neutrophils, induced by
zymosan alone or by combined LPS and
zymosan treatment. Early treatment with PAF antagonists may be beneficial in preventing the development of
acute lung injury in humans.