Metabolic aspects of endotoxin as a model of septic shock: Approached from oxidative stress

Abstract

Despite the remarkable progress in intensive care medicine, sepsis and shock continue to be major clinical problems in intensive care units. Septic shock may be associated with a toxic state initiated by the stimulation of monocytes by bacterial toxins such as endotoxin, which is released into the bloodstream. This study describes the role of oxidative stress in endotoxin-induced metabolic disorders. We demonstrate that endotoxin injection results in lipid peroxide formation and membrane injury in experimental animals, causing decreased levels of free radical scavengers or quenchers. Interestingly, it was also suggested that tumor necrosis factor (TNF)-induced oxidative stress occurs as a result of bacterial or endotoxin translocation under conditions of reduced reticuloendothelial system function in various disease states. In addition, we suggest that intracellular Ca2+, Zn2+, or selenium levels may participate, at least in part, in the oxidative stress during endotoxemia. On the other hand, it is also suggested that the extent of endotoxin-induced nitric oxide (NO) formation may be due, at least in part, to a change in heme metabolic regulation during endotoxemia. However, in our experimental model, NO is not crucial for lipid peroxide formation during endotoxemia. Sho-saiko-to is one of the most frequently prescribed Kampo medicines and has primarily been used to treat chronic hepatitis. We report that Sho-saiko-to decreases the rh TNF-induced lethality in galactosamine-hypersensitized mice and protects mice against oxygen toxicity and Ca2+ overload in the cytoplasm or mitochondria during endotoxemia. We further suggest that Sho-saiko-to shows a suppressive effect on NO generation in macrophages stimulated with endotoxin and that it may be useful in improving endotoxin shock symptoms. © 2004 The Pharmaceutical Society of Japan.