title: Systemic pro-inflammatory cytokine status following therapeutic hypothermia in a piglet hypoxia-ischemia model.
abstract: Inflammatory cytokines are implicated in the pathogenesis of perinatal hypoxia-ischemia (HI). The influence of hypothermia (HT) on cytokines after HI is unclear. Our aim was to assess in a piglet asphyxia model, under normothermic (NT) and HT conditions: (i) the evolution of serum cytokines over 48 h and (ii) cerebrospinal fluid (CSF) cytokine levels at 48 h; (iii) serum pro/anti-inflammatory cytokine profile over 48 h and (iv) relation between brain injury measured by magnetic resonance spectroscopy (MRS) and brain TUNEL positive cells with serum cytokines, serum pro/anti-inflammatory cytokines and CSF cytokines.
  
  
  
  Newborn piglets were randomized to NT (n = 5) or HT (n = 6) lasting 2-26 h after HI. Serum samples were obtained 4-6 h before, during and at 6-12 h intervals after HI; CSF was obtained at 48 h. Concentrations of interleukin (IL)-1β, -4, -6, -8, -10 and TNF-α were measured and pro/anti-inflammatory status compared between groups. White matter and thalamic voxel lactate/N-acetyl aspartate (Lac/NAA) (a measure of both oxidative metabolism and neuronal loss) were acquired at baseline, after HI and at 24 and 36 h.
  
  
  
  Lac/NAA was reduced at 36 h with HT compared to NT (p = 0.013 basal ganglia and p = 0.033 white matter). HT showed lower serum TNF-α from baseline to 12 h (p < 0.05). Time-matched (acquired within 5 h of each other) serum cytokine and MRS showed correlations between Lac/NAA and serum IL-1β and IL-10 (all p < 0.01). The pro/anti-inflammatory ratios IL-1β/IL-10, IL-6/IL-10, IL-4/IL-10 and IL-8/IL-10 were similar in NT and HT groups until 36 h (24 h for IL-6/IL-10); after this, 36 h pro/anti-inflammatory cytokine ratios in the serum were higher in HT compared to NT (p < 0.05), indicating a pro-inflammatory cytokine surge after rewarming in the HT group. In the CSF at 48 h, IL-8 was lower in the HT group (p < 0.05). At 48 h, CSF TNF-α correlated with Lac/NAA (p = 0.02) and CSF IL-8 correlated with white matter TUNEL positive cell death (p = 0.04).
  
  
  
  Following cerebral HI, there was a systemic pro-inflammatory surge after rewarming in the HT group, which is counterintuitive to the putative neuroprotective effects of HT. While serum cytokines were variable, elevations in CSF inflammatory cytokines at 48 h were associated with MRS Lac/NAA and white matter cell death.
authors.affiliation: Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK.
authors.forename: Eridan
authors.initials: E
authors.lastname: Rocha-Ferreira
authors.affiliation: Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK.|First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Dorottya
authors.initials: D
authors.lastname: Kelen
authors.affiliation: Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Faulkner
authors.affiliation: Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Broad
authors.affiliation: Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK.
authors.forename: Manigandan
authors.initials: M
authors.lastname: Chandrasekaran
authors.affiliation: Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK.|First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Áron
authors.initials: Á
authors.lastname: Kerenyi
authors.affiliation: Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK.
authors.forename: Takenori
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Medical Physics and Bioengineering, and Institute of Neurology, University College London, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Bainbridge
authors.affiliation: Institute of Neurology, University College London, London, UK.
authors.forename: Xavier
authors.initials: X
authors.lastname: Golay
authors.affiliation: Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Sullivan
authors.affiliation: Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK.|Institute of Oncology and Developmental Biology, Institute of Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
authors.affiliation: Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK. n.robertson@ucl.ac.uk.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Robertson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D016207:Cytokines / Q000097:blood* / Q000134:cerebrospinal fluid*; D004195:Disease Models, Animal; D007036:Hypothermia, Induced / Q000379:methods / Q000639:trends*; D020925:Hypoxia-Ischemia, Brain / Q000097:blood* / Q000134:cerebrospinal fluid*; D018836:Inflammation Mediators / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D013552:Swine
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators
keywords: Biomarkers; Birth asphyxia; Cytokines; Magnetic resonance spectroscopy; Neuroprotection; Therapeutic hypothermia