aerobically respiring cells. The enzyme catalyzing this transition metals iron and copper in its active site. These ions can be paramagnetic and contain stable unpaired electrons. By using the unpaired electrons in these transition metals to control the O2 reactions, mitochondria prevent the unwanted release of ROS. In sepsis, there are several potential sources of ROS, including the mitochondrial respiratory electron transport chain, xanthine oxidase activation as a result of ischemia and reperfusion, the respiratory burst associated with immune cell activation, arachidonic acid metabolism and NADPH oxidase. In fact, activated immune cells produce O2 - as a cytotoxic agent as part of the respiratory burst via the action of membrane-bound NADPH oxidase on O2. The increase of ROS after LPS challenge has been demonstrated in different models of septic shock in peritoneal macrophages and lymphocytes. This disturbance in the balance between pro-oxidants (ROS) and antioxidants in favor of the former is characteristic of oxidative stress in immune cells in response to endotoxin. In this context, a typical behavior of these cells under an oxidative stress situation implies changes in different immune functions such as an increase in adherence and phagocytosis and a decrease in chemotaxis . Neutrophils play a crucial role in the primary immune defense against infectious agents,which includes phagocytosis and the production of ROS.

## Antioxidant Defenses

Antioxidants are central to the redox balance in the human body. They do not act in isolation, but synergistically with other classes of molecules. Primary antioxidants prevent oxygen radical formation, by either removing free radical precursors or by inhibiting catalysis, e.g. the enzymes glutathione peroxidase and catalase. Secondary antioxidants react with ROS which have already been formed, either to remove or inhibit them, e.g. vitamins C and E. Endogenous antioxidant defenses exist in a number of locations, namely intracellularly, on the cell membrane and extracellularly. The immune system is highly reliant on accurate cell-cell communication for optimal function, and any damage to the signaling systems involved will result in an impaired immune responsiveness. Oxidant-mediated tissue injury is a particular hazard to the immune system, since phagocyte cells produce ROS as part of the defense against infection. Therefore, adequate amounts of neutralizing antioxidants are required to prevent damage to the immune cells themselves. The SOD enzymes are a family of metalloenzymes which rapidly promote the conversion of O2- to H2O2. Three forms of SOD are recognized to be important: copper-zinc SOD (cytoplasmic-located), manganese SOD (mitochondrial-located) and extracellular SOD (extracellular matrix-located). Catalase and glutathione peroxidase, a selenium containig enzyme which requires the presence of reduced GSH for its action, both catalyze the conversion of H2O2 to H 2O. GSH also has direct antioxidant activity, through donation of hydrogen ions, to repair damaged DNA. Oxidative stress and modulation on GSH/GSSG (GSSG=oxidized GSH) levels also up-regulate gene expression of several other antioxidant proteins, such as manganese SOD, glutathione peroxidase, thioredoxin (Trx) and metallothionein.