Leukotoxin is clinically associated with
acute respiratory distress syndrome (ARDS). Recently, we found that
leukotoxin-diol, the hydrated product of
leukotoxin, is more toxic than the parent
leukotoxin in vitro (Moghaddam and colleagues, Nature Med. 1997;3:562-566). To test if this difference in the 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 animals exposed to
leukotoxin at the same dose survived. Histopathologic evaluation of the lungs revealed massive alveolar
edema and
hemorrhage with interstitial
edema around blood vessels in the lungs of mice treated with
leukotoxin-diol, whereas the lungs of mice treated with identical doses of
leukotoxin had perivascular
edema only and little change in alveolar spaces. Immunohistochemistry showed that the soluble
epoxide hydrolase responsible for the hydrolysis of
leukotoxin to its diol is concentrated in the vascular smooth muscle of small and medium-sized pulmonary vessels. In addition,
4-phenylchalcone oxide, an inhibitor of soluble
epoxide hydrolase, was found to decrease the mortality induced by
leukotoxin but had no effect on mortality induced by
leukotoxin-diol. These studies provide strong in vivo evidence that
leukotoxin may act as a protoxicant and that the corresponding diol is a putative toxic mediator involved in the development of ARDS.