Reactive oxygen species and the MEK/ERK pathway are involved in the toxicity of clostridium perfringens-toxin, a prototype bacterial phospholipase C

Abstract

Clostridium perfringens, the most broadly distributed pathogen in nature, produces a prototype phospholipase C, also called-toxin, which plays a key role in the pathogenesis of gas gangrene.-Toxin causes plasma membrane disruption at high concentrations, but the role of intracellular mediators in its toxicity at low concentrations is unknown. This work demonstrates that-toxin causes oxidative stress and activates the MEK/ERK pathway in cultured cells and furthermore provides compelling evidence that O2-., hydrogen peroxide, and the OH. radical are involved in its cytotoxic and myotoxic effects. The data show that antioxidants and MEK1 inhibitors reduce the cytotoxic and myotoxic effects of-toxin and demonstrate that edaravone, a clinically used hydroxyl radical trap, reduces the myonecrosis and the mortality caused by an experimental infection with C. perfringens in a murine model of gas gangrene. This knowledge provides new insights for the development of novel therapies to reduce tissue damage during clostridial myonecrosis. © 2012 The Author.