Leukotoxin-diol - A putative toxic mediator involved in acute respiratory distress syndrome

Leukotoxin is clinically associated with acute respiratory distress syndrom e (ARDS). Recently, we found that leukotoxin-diol, the hydrated product of leukotoxin, is more toxic than the parent leukotoxin in vitro (Moghaddam an d colleagues, Nature Med. 1997;3:562-566). To test if this difference in th e toxicity of leukotoxin and leukotoxin-diol exists in vivo, Swiss Webster mice were administered leukotoxin or leukotoxin-diol. All mice treated with leukotoxin-diol died of ARDS-like respiratory distress, whereas the animal s exposed to leukotoxin at the same dose survived. Histopathologic evaluati on of the lungs revealed massive alveolar edema and hemorrhage with interst itial edema around blood vessels in the lungs of mice treated with leukotox in-diol, whereas the lungs of mice treated with identical doses of leukotox in had perivascular edema only and little change in alveolar spaces. Immuno histochemistry showed that the soluble epoxide hydrolase responsible for th e hydrolysis of leukotoxin to its dial is concentrated in the vascular smoo th muscle of small and medium-sized pulmonary vessels. In addition, 4-pheny lchalcone oxide, an inhibitor of soluble epoxide hydrolase, was found to de crease the mortality induced by leukotoxin but had no effect on mortality i nduced by leukotoxin-diol. These studies provide strong in vivo evidence th at leukotoxin may act as a protoxicant and that the corresponding dial is a putative toxic mediator involved in the development of ARDS.