• G McCreath, M M F Scullion, D A Lowes, N R Webster, and H F Galley.
• Academic Unit of Anaesthesia and Intensive Care, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
• Br J Anaesth. 2016 Jan 1;116(1):131-9.

BackgroundMitochondrial oxidative stress has a role in sepsis-induced organ dysfunction. The endogenous mechanisms to initiate protective pathways are controlled by peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1α) and nuclear factor erythroid 2-like 2 (NFE2L2). Activation of these pathways are potential therapeutic targets in sepsis. We used pharmacological activators to determine the effects on markers of mitochondrial damage and inflammation in human endothelial cells under conditions of sepsis.MethodsHuman endothelial cells were exposed to lipopolysaccharide plus peptidoglycan G to mimic a sepsis environment, with a range of concentrations of a selective synthetic agonist of silent information regulator-1 (SIRT-1) which activates PGC1α, or bis(2-hydroxy-benzylidene) acetone (2HBA) which activates NFE2L2, with and without inhibitors of these pathways. Cells were cultured for up to seven days and we measured mitochondrial membrane potential, metabolic activity, and density (as a marker of biogenesis), interkeukin-6 (to reflect inflammation) and glutathione (as a measure of antioxidant status).ResultsUnder conditions mimicking sepsis, activation of the PGC1α and NFE2L2 pathways protected cells from LPS/PepG-induced loss of mitochondrial membrane potential (P=0.0002 and P=0.0009, respectively) and metabolic activity (P=0.05 and P<0.0001, respectively), and dampened interleukin-6 responses (P=0.003 and P=0.0001, respectively). Mitochondrial biogenesis (both P=0.0001) and glutathione (both P<0.0001) were also increased. These effects were blunted by the respective inhibitors.ConclusionsThe development of organ dysfunction during human sepsis is linked to mitochondrial dysfunction, and so activation of PGC1α/NFE2L2 is likely to be beneficial. These pathways are attractive therapeutic targets for sepsis.© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

28 keywords...

hide…