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1 Wolfson Institute of Biomedical Research, University College London, London, United Kingdom
2 Histopathology, University College London, London, United Kingdom
3 Wolfson Institute of Biomedical Research, University College London, London, United Kingdom; Dept of Medicine, University College London, London, United Kingdom
4 Heart Science Centre, Imperial College London, Harefield, Middlesex, United Kingdom; Biochemistry, Medical University, Gdansk, Poland
* To whom correspondence should be addressed. E-mail: m.singer{at}ucl.ac.uk.
Although sepsis is the major cause of mortality and morbidity in the critically ill, precise mechanism(s) causing multi-organ dysfunction remain unclear. Findings of impaired oxygen utilization in septic patients and animals implicate nitric oxidemediated 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, fluidresuscitated, fecal peritonitis model utilising male Wistar rats, that closely replicates human physiologic, biochemical and histologic findings with a 40% mortality. As with humans, the severity of organ dysfunction and eventual poor outcome were associated with nitric oxide over-production and increasing mitochondrial dysfunction (Complex I inhibition and adenosine triphosphate depletion). This was seen in both vital (liver) and 'non-vital' (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 which will facilitate future translational research.
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