The purposes of this proposal are two fold. The first objective is to assess specific roles for generation of reactive oxygen species (ROS), particularly in the extracellular space, in the pathogenesis of pulmonary and other organ dysfunction in sepsis syndrome. The second objective is to determine if the tissue injury can be ameliorated by antioxidant therapy directed at these effects. Sepsis syndrome is a pathological systemic response leading to hemodynamic and metabolic failure after the intravascular release of endotoxin or other toxic products from microorganisms. Despite advances in antibiotic and intensive supportive therapy over the past two decades, half of the patients with sepsis syndrome will die from multiple organ dysfunction even with appropriate therapy. Previous studies have led to descriptions of systemic derangements in gas exchange, hemodynamic parameters, oxygen uptake and substrate preference at various stages of sepsis. The mechanisms of sepsis-induced alterations in oxygen delivery, oxygen metabolism and energy provision are poorly understood at the tissue level in vivo, particularly when ARDS and multiple organ dysfunction syndrome accompany sepsis. These inflammatory syndromes produce mediators that induce significant oxidative stress on the tissues by both extracellular and intracellular processes. These oxidative processes include generation of superoxide, hydrogen peroxide and nitric oxide by various cell types in addition to cellular oxygen utilization for energetic purposes. The intracellular generation of reactive species of oxygen by mitochondria and other sources during progression of sepsis syndrome exacerbates the oxidative stress and injury. We will evaluate these oxidative mechanisms of organ injury to determine oxidative stress relative to metabolism in sepsis vulnerable tissues such as lung, liver and muscle in two existing animal models. One model, the rodent cecal ligation-puncture (CLP) model provides an approach to study the mechanisms of oxidant product, sites of oxidative damage and preliminary effects of antioxidant compounds. The other model, the baboon model of E. coli sepsis, allows access a clinically relevant model to permit testing of novel and rational therapies based on antioxidant mechanisms.
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