Am. J. Respir. Cell Mol. Biol., Volume 25, Number 4, October, 2001 434-438

Leukotoxin-Diol
A Putative Toxic Mediator Involved in Acute Respiratory Distress Syndrome

Jiang Zheng, Charles G. Plopper, Jeffery Lakritz, David H. Storms, and Bruce D. Hammock

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts; Departments of Entomology, and Anatomy, Physiology, and Cell Biology, University of California, Davis, California; and Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri-Columbia, Columbia, Missouri

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.

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