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INFLAMMATION, CYTOKINES, AND TEMPERATURE REGULATION

Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure

¹Bloomsbury Institute of Intensive Care Medicine, Wolfson Institute of Biomedical Research and Department of Medicine, University College London, London WC1E 6BT; ²Department of Histopathology, University College London Hospitals National Health Service Trust, London WC1E 6JJ; and ³Heart Science Centre, Imperial College at Harefield Hospital, London UB9 6JH, United Kingdom; and Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland

Submitted 1 August 2003 ; accepted in final form 4 November 2003

Although sepsis is the major cause of mortality and morbidity in the critically ill, precise mechanism(s) causing multiorgan dysfunction remain unclear. Findings of impaired oxygen utilization in septic patients and animals implicate nitric oxide-mediated inhibition of the mitochondrial respiratory chain. We recently reported a relationship between skeletal muscle mitochondrial dysfunction, clinical severity, and poor outcome in patients with septic shock. We thus developed a long-term, fluid-resuscitated, fecal peritonitis model utilizing male Wistar rats that closely replicates human physiological, biochemical, and histological findings with a 40% mortality. As with humans, the severity of organ dysfunction and eventual poor outcome were associated with nitric oxide overproduction and increasing mitochondrial dysfunction (complex I inhibition and ATP depletion). This was seen in both vital (liver) and nonvital (skeletal muscle) organs. Likewise, histological evidence of cell death was lacking, suggesting the possibility of an adaptive programmed shutdown of cellular function. This study thus supports the hypothesis that multiorgan dysfunction induced by severe sepsis has a bioenergetic etiology. Despite the well-recognized limitations of laboratory models, we found clear parallels between this long-term model and human disease characteristics that will facilitate future translational research.

nitric oxide; adenosine 5'-triphosphate; respiratory chain; complex I; glutathione

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