Inflammatory-induced hibernation in the fetus: priming of fetal sheep metabolism correlates with developmental brain injury.

Prenatal inflammation is considered an important factor contributing to preterm birth and neonatal mortality and morbidity. The impact of prenatal inflammation on fetal bioenergetic status and the correlation of specific metabolites to inflammatory-induced developmental brain injury are unknown. We used a global metabolomics approach to examine plasma metabolites differentially regulated by intrauterine inflammation. Preterm-equivalent sheep fetuses were randomized to i.v. bolus infusion of either saline-vehicle or LPS. Blood samples were collected at baseline 2 h, 6 h and daily up to 10 days for metabolite quantification. Animals were killed at 10 days after LPS injection, and brain injury was assessed by histopathology. We detected both acute and delayed effects of LPS on fetal metabolism, with a long-term down-regulation of fetal energy metabolism. Within the first 3 days after LPS, 121 metabolites were up-regulated or down-regulated. A transient phase (4-6 days), in which metabolite levels recovered to baseline, was followed by a second phase marked by an opposing down-regulation of energy metabolites, increased pO(2) and increased markers of inflammation and ADMA. The characteristics of the metabolite response to LPS in these two phases, defined as 2 h to 2 days and at 6-9 days, respectively, were strongly correlated with white and grey matter volumes at 10 days recovery. Based on these results we propose a novel concept of inflammatory-induced hibernation of the fetus. Inflammatory priming of fetal metabolism correlated with measures of brain injury, suggesting potential for future biomarker research and the identification of therapeutic targets.

Activation of the hypothalamic-pituitary-adrenal axis and autonomic nervous system during inflammation and altered programming of the neuroendocrine-immune axis during fetal and neonatal development: lessons learned from the model inflammagen, lipopolysaccharide.

The hypothalamic-pituitary-adrenal axis (HPAA) and autonomic nervous system (ANS) are both activated during inflammation as an elaborate multi-directional communication pathway designed to restore homeostasis, in part, by regulating the inflammatory and subsequent immune response. During fetal and neonatal development programming of the HPAA, ANS and possibly the immune system is influenced by signals from the surrounding environment, as part of an adaptive mechanism to enhance the survival of the offspring. It is currently hypothesized that if this programming is either misguided, or the individual's environment is drastically altered such that neuroendocrine programming becomes maladaptive, it may contribute to the pathogenesis of certain diseases. Current research, suggests that exposure to inflammatory signals during critical windows of early life development may influence the programming of various genes within the neuroendocrine-immune axis. This review will provide, (1) an overview of the HPAA and ANS pathways that are activated during inflammation, highlighting studies that have used lipopolysaccharide as a model inflammagen and, (2) evidence to support the hypothesis that inflammatory stress during fetal and neonatal development can alter programming of the neuroendocrine-immune axis, influencing stress and immune responsiveness, and possibly disease resistance later in life.

Expression of C/EBP delta in rat liver during development and the acute-phase response.

Using Western analysis, C/EBP delta was established in the nuclear extract and nuclear matrix throughout rat liver development and in the adult. During the acute-phase response (APR), C/EBP delta increased in the nuclear extract but remained unchanged in the nuclear matrix of fetal and postnatal rats, whereas it increased in both the nuclear extract and nuclear matrix of the adult. The solubility partitioning of gene regulatory proteins in the nucleus is important for their functioning (Uskokovic et al. 2002). The obtained different solubility partitioning profiles of C/EBP delta suggest that its activity is regulated by different mechanisms during development and in the adult.