The role of endotoxin, the TNF family of cytokines and
intracellular pH in perinatal hypoxic-ischemic brain injury.
Doctoral thesis, UCL (University College London).
To explore the effect of endotoxin as a sensitising agent prior to neonatal hypoxiaischemia differing doses of endotoxin (E. coli lipopolysaccharide, LPS) were given to neonatal mice prior to hypoxia-ischemia, with sensitising effects noted at dosages of 0.3mg/kg of LPS or higher. Varying the time interval between endotoxin administration and hypoxia-ischemia demonstrated that LPS given between 4 and 12 hours before hypoxia-ischemia had a sensitising effect on subsequent hypoxia ischemia. In contrast, LPS given at the time of or 24 hours before hypoxia-ischemia did not. To help understand the mechanism by which this sensitising effect occurs, a dose-response study of LPS alone was undertaken. Here, a dose-dependent activation of microglia was demonstrated throughout the brain, particularly in the thalamus and cortex, by 12 hours following endotoxin administration. There was also evidence of vascular endothelial activation (ICAM1) as early as 4 hours after endotoxin administration. To study the role of the TNF cluster of cytokines (TNF alpha, lymphotoxin alpha and lymphotoxin beta), animals with a deletion of the entire TNF cluster were examined. Deletion of the TNF cluster was shown to abolish both endotoxin-mediated sensitisation of the developing brain to subsequent hypoxia, and to prevent upregulation of macrophage and vascular endothelium by endotoxin alone. This study also examined the effects of hypoxia-ischemia on intracellular pH. Increasing duration of hypoxia-ischemia resulted in a progressive intracellular acidosis within the brain, initially ipsilateral to the carotid ligation, but becoming bilateral with prolonged hypoxia. In the reoxygenation phase, there was a rebound intracellular alkalosis at 6 hours of reoxygenation across the whole forebrain. Previous studies have suggested that this alkalosis is mediated by a Na+/H+ exchanger. Blockade of this transporter with N-methyl isobutyl amiloride prior to hypoxia-ischemia was shown to confer neuroprotection in the developing brain.
|Title:||The role of endotoxin, the TNF family of cytokines and intracellular pH in perinatal hypoxic-ischemic brain injury|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Women's Health|
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