Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure.
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.
Brealey
David
D
Bloomsbury Institute of Intensive Care Medicine, Wolfson Institute of Biomedical Research, Department of Medicine, University College London, London WC1E 6BT, United Kingdom.
Karyampudi
Sekhar
S
Jacques
Thomas S
TS
Novelli
Marco
M
Stidwill
Ray
R
Taylor
Val
V
Smolenski
Ryszard T
RT
Singer
Mervyn
M
D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D001794:Blood Pressure / Q000502:physiology; D001806:Blood Urea Nitrogen; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D005978:Glutathione / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D009102:Multiple Organ Failure / Q000473:pathology / Q000503:physiopathology*; D009566:Nitrates / Q000378:metabolism; D010538:Peritonitis / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors
D015415:Biomarkers; D009566:Nitrates; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D003404:Creatinine; D005978:Glutathione