title: Pharmacological activation of endogenous protective pathways against oxidative stress under conditions of sepsis.
abstract: BACKGROUND
  Mitochondrial 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.
  
  
  METHODS
  Human 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).
  
  
  RESULTS
  Under 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Academic Unit of Anaesthesia and Intensive Care, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
authors.forename: G
authors.initials: G
authors.lastname: McCreath
authors.affiliation: Academic Unit of Anaesthesia and Intensive Care, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
authors.forename: M M F
authors.initials: MM
authors.lastname: Scullion
authors.affiliation: Academic Unit of Anaesthesia and Intensive Care, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK Now at CXR Biosciences Ltd., Dundee DD1 5JJ, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Lowes
authors.affiliation: Academic Unit of Anaesthesia and Intensive Care, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
authors.forename: N R
authors.initials: NR
authors.lastname: Webster
authors.affiliation: Academic Unit of Anaesthesia and Intensive Care, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK h.f.galley@abdn.ac.uk.
authors.forename: H F
authors.initials: HF
authors.lastname: Galley
mesh_terms: D000096:Acetone / Q000031:analogs & derivatives / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018805:Sepsis / Q000378:metabolism*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001593:Benzyl Compounds; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C518535:bis(2-hydroxybenzylidene)acetone; D000096:Acetone; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: antioxidants; endothelial cells; oxidative stress; sepsis