Abstract
BackgroundInflammatory 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.MethodsNewborn 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.ResultsLac/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).ConclusionsFollowing 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.
Highlights
Inflammatory cytokines are implicated in the pathogenesis of perinatal hypoxia-ischemia (HI)
Our aim was to use a preclinical piglet model which has a similar level of brain maturation to term human newborns, under normothermic (NT) and HT conditions with a standardized cerebral hypoxic-ischemic insult to assess (i) the evolution of serum cytokines and (ii) cerebrospinal fluid (CSF) cytokine levels, (iii) pro- versus anti-inflammatory serum cytokine profiles over 48 h and (iv) the relation between brain injury severity measured by cerebral proton (1H) magnetic resonance spectroscopy (MRS) and brain TUNEL positive cells with the cytokine concentrations in serum and CSF
Brain injury as measured by MRS and TUNEL positive cells was associated with some pro-inflammatory cytokines (IL-1β, IL-8) but the pro/anti-inflammatory ratios were not associated with lactate/N-acetyl aspartate (Lac/NAA) apart from a weak correlation with Tumour necrosis factor alpha (TNF-α)/IL-10
Summary
Inflammatory cytokines are implicated in the pathogenesis of perinatal hypoxia-ischemia (HI). Early peaks in IL-6 and monocyte MCP-1 within 0– 9 h were predictive of adverse outcome, Jenkins et al described a second peak in IL-6 and macrophage inflammatory protein (MIP)-1 alpha in HT patients who went on to have a good outcome [6]. These data suggest that cytokine levels may be specific to the phase of injury and repair and that cytokines may switch roles within a relatively short time after delivery
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