title: Hypothermia protects brain mitochondrial function from hypoxemia in a murine model of sepsis.
abstract: Sepsis is commonly associated with brain dysfunction, but the underlying mechanisms remain unclear, although mitochondrial dysfunction and microvascular abnormalities have been implicated. We therefore assessed whether cerebral mitochondrial dysfunction during systemic endotoxemia in mice increased mitochondrial sensitivity to a further bioenergetic insult (hyoxemia), and whether hypothermia could improve outcome. Mice (C57bl/6) were injected intraperitoneally with lipopolysaccharide (LPS) (5 mg/kg; n = 85) or saline (0.01 ml/g; n = 47). Six, 24 and 48 h later, we used confocal imaging in vivo to assess cerebral mitochondrial redox potential and cortical oxygenation in response to changes in inspired oxygen. The fraction of inspired oxygen (FiO2) at which the cortical redox potential changed was compared between groups. In a subset of animals, spontaneous hypothermia was maintained or controlled hypothermia induced during imaging. Decreasing FiO2resulted in a more reduced cerebral redox state around veins, but preserved oxidation around arteries. This pattern appeared at a higher FiO2in LPS-injected animals, suggesting an increased sensitivity of cortical mitochondria to hypoxemia. This increased sensitivity was accompanied by a decrease in cortical oxygenation, but was attenuated by hypothermia. These results suggest that systemic endotoxemia influences cortical oxygenation and mitochondrial function, and that therapeutic hypothermia can be protective.
authors.affiliation: Institute of Neurology, University College London, UK k.chisholm@ucl.ac.uk.
authors.forename: Kim I
authors.initials: KI
authors.lastname: Chisholm
authors.affiliation: Institute of Neurology, University College London, UK.|Anaesthesiology LIM-8, Medical School, University of São Paulo, Brazil.
authors.forename: Keila K
authors.initials: KK
authors.lastname: Ida
authors.affiliation: Institute of Neurology, University College London, UK.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Davies
authors.affiliation: Medical Physics and Biomedical Engineering, University College London, UK.
authors.forename: Ilias
authors.initials: I
authors.lastname: Tachtsidis
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Ireland.
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Papkovsky
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, University College London, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Dyson
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, University College London, UK.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.affiliation: Cell and Developmental Biology, University College London, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.affiliation: Institute of Neurology, University College London, UK.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D001831:Body Temperature; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D007036:Hypothermia, Induced; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D018805:Sepsis / Q000150:complications / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control
chemical_list: D010100:Oxygen
keywords: Imaging; hypothermia; inflammation; microcirculation; microscopy