Hara 2013 Eur J Anaesthesiol
|Hara N, Karlsson M, Sjövall F, Hansson Magnus J, Elmér E, Uchino H (2013) Early brain mitochondrial dysfunction in a mouse model of sepsis: 7AP4‐9. Eur J Anaesthesiol 30,112-112.
Abstract: The pathogenesis of sepsis-induced multiple organ failure is complex and our understanding of the pathophysiology is incomplete. The theory of cytopathic hypoxia suggests mitochondrial dysfunction as part of the etiology caused by an inability to utilize available oxygen. It has been shown that sepsis can induce brain mitochondrial dysfunction by increased uncoupling of the oxidative phosphorylation system. The aim of the present study was to evaluate the temporal dynamics of brain mitochondrial function in a mouse model of sepsis.
The ethical committee of animal experiments at Tokyo Medical University (H-24013) approved the study. Sepsis was induced by cecal ligation and puncture (CLP) and controls were sham operated. Using high-resolution respirometry (Oroboros Oxygraph-2k) brain homogenates from 30 C57BL/6 mice were analyzed at either 6 h or 24 h. ROS-production was measured simultaneously using fluorometry (Oroboros LED2 module). An analysis protocol of complex-specific substrates and inhibitors examined the role of the individual respiratory complexes as well as the uncoupled maximal respiratory capacity not restricted by phosphorylation.
In the 6-hour group there was a statistically significant increase in the oligomycin-induced LEAK state in septic mice compared to controls (P = 0.037) and a trend to lower complex I function in the sepsis group (P = 0.124) which resulted in a decreased respiratory control ratio (P = 0.043). At the 24-hour time point there was also a trend to lower complex I function in the sepsis group (P = 0.077) and a minor non-significant increase in the LEAK state (P = 0.262) resulting in a statistically significant decreased respiratory control ratio (P = 0.029). The convergent complex I+II, maximum uncoupled capacity of the electron transfer-pathway, uncoupled complex II and complex IV showed similar results when comparing septic mice to controls at both time-points. Furthermore the data indicates that there was no dif ference in ROS-production between the groups.
The present study demonstrates that sepsis induces an early brain mitochondrial dysfunction by reducing the respiratory ef ficiency, i.e. the coupling of oxidative phosphorylation.
Labels: MiParea: Respiration Pathology: Sepsis Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Nervous system Preparation: Homogenate
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, CIV, NS HRR: Oxygraph-2k, O2k-Fluorometer