Endotoxemia in transgenic mice overexpressing human glutathione peroxidases

In response to endotoxemia induced by administration of lipopolysaccharide, a complex series of reactions occurs in mammalian tissues. During this inf lammation response, cells produce different mediators, such as reactive oxy gen species, a number of arachidonic acid metabolites, and cytokines. The r eactive oxygen species thus generated have been suggested to produce tissue injury as a result of macromolecular damage or by interfering with regulat ory processes. They may also act as important signaling molecules to induce redox-sensitive genes. We report here that transgenic mice overexpressing 2 major forms of human glutathione peroxidases (GPs), intra- and extracellu lar GP, are able to modulate host response during endotoxemic conditions. W e show that these animals have a decreased hypotension and increased surviv al rate after administration of a high dosage of lipopolysaccharide. Overex pression of GPs alters vascular permeability and production of cytokines (i nterleukin-1 beta and tumor necrosis factor-alpha) and NO, affects arachido nic acid metabolism, and inhibits leukocyte migration. These results sugges t an important role for peroxides in pathogenesis during endotoxemia, and G Ps, by regulating their level, may prove to be good candidates for antioxid ant therapy to protect against such injury.