Metabolic theory of septic shock

Figure 1 Septic shock begins with a systemic inflammatory reaction to an infection. A contemporaneous increase in metabolism is initiated, which can deplete reserves of critical nutrients such as glutathione. Glutathione is crucial for the neutralization of H₂O₂, a toxic, membrane-permeable oxidizing agent generated as a by-product of cellular metabolism. Depletion of cellular glutathione results in elevation of H₂O₂ which can diffuse out of organ parenchymal cells and into capillary endothelium before reaching the bloodstream. Once in the systemic circulation, excess H₂O₂ is distributed throughout the body resulting in systemic oxidative damage to plasma components, organs and blood vessels. The net result is H₂O₂ induced coagulopathy, immunocyte apoptosis and microvascular dysfunction leading to disseminated intravascular coagulation, immunosuppression, organ failure and septic shock respectively. H₂O₂ inhibits GPx and catalase, which are critical anti-oxidant enzymes required for H₂O₂ neutralization. This prevents restoration of normal plasma and tissue redox balance while exacerbating oxidative tissue damage. H₂O₂ can also activate nuclear factor-κB (NF-κB) contributing to the inappropriate activation of this master pro-inflammatory transcription factor observed in septic shock. The pathologic activation of NF-kB contributes to elevated tumor necrosis factor-alpha levels, another potent generator of intracellular H₂O₂. GPx: Glutathione peroxidase.