Elucidating the Early Signal Transduction Pathways Leading to Fetal Brain Injury in Preterm Birth

Abstract

Adverse neurologic outcome, including cerebral palsy, is a significant contributor to long-term morbidity in preterm neonates. However, the mechanisms leading to brain injury in the setting of a preterm birth are poorly understood. In the last decade, there has been a growing body of evidence correlating infection or inflammation with preterm birth. The presence of intrauterine inflammation significantly increases the risk for adverse neurologic outcome in the neonate. These studies were performed to elucidate the early signal transduction pathways activated in the fetal brain that may result in long-term neurologic injury. Using our mouse model of localized intrauterine inflammation, the activation of TH1/TH2 pathways in the placenta, fetus corpus, fetal liver, and fetal brain was investigated. Additional studies determined whether activation of TH1/TH2 pathways could promote cell death and alter glial development. Real-time PCR studies demonstrated that a robust TH1/TH2 response occurs rapidly in the fetal brain after exposure to intrauterine inflammation. The cytokine response in the fetus and placenta was not significantly correlated with the response in the fetal brain. Along with an immune response, cell death pathways were activated early in the fetal brain in response to intrauterine LPS. Implicating TH1/TH2 and cell death pathways in permanent brain injury are our findings of an increase in GFAP mRNA and protein as well as a loss of pro-oligodendrocytes. With increased understanding of the mechanisms by which inflammation promotes brain injury in the preterm neonate, identification of potential targets to limit adverse neonatal outcomes becomes possible. (Pediatr Res 59: 50-55, 2006)

TLR-4-Dependent and -Independent Mechanisms of Fetal Brain Injury in the Setting of Preterm Birth

“…53,54 Using this mouse model, we have demonstrated that intrauterine inflammation induces a cytokine response in the fetal brain along with evidence of white matter injury. 55 Novel to our laboratory, we have also demonstrated that while intrauterine inflammation does not cause overt structural brain injury, 56 it does promote a specific neuronal insult. 57 Furthermore, we have demonstrated that this observed brain injury is present only in the setting of inflammation-induced preterm birth as preterm parturition from a noninflammatory stimulus does not cause brain injury.…”

“…To assess expression of neuronal markers, quantitative polymerase chain reaction (qPCR) was performed using equivalent dilutions of each sample on the Applied Biosystems Model 9700 sequence detector PCR machine, as reported previously. 55,63,64 Primer sets to neuronal markers MAP-2 and nestin, conjugated to Taqman MGB probes, were used for qPCR (Applied Biosystems). The relative abundance of the target of interest was divided by the relative abundance of 18S in each sample to generate a normalized abundance for the target of interest.…”

Nod1 Activation by Bacterial iE-DAP Induces Maternal–Fetal Inflammation and Preterm Labor

“…In general, infections and infectious components trigger inflammation and preterm labor in mice; however, the type of stimuli used, as well as the timing and the dose administered, may determine the type of response generated and the tissues involved. For example, high-dose LPS delivered late in gestation (ED 14-17) induces preterm labor associated with placental and fetal inflammation (38)(39)(40), whereas heat-killed Escherichia coli induces preterm labor and uterine inflammation, without changes in placental or fetal cytokines (41,42). In contrast, infection with Ureaplasma late in gestation induces placental and fetal inflammation without preterm labor (43), whereas viral infection early in gestation (ED 8.5) triggers fetal and maternal splenic inflammation, without inducing placental inflammation or preterm labor (44).…”

A Mouse Model of Term Chorioamnionitis Unraveling Causes of Adverse Neurological Outcomes

“…Animal models have been designed to elucidate the effect of inflammation on fetal and neonatal brain development. [17][18][19][36][37][38] However, these are either systemic models of inflammation with intraperitoneal infusion of LPS 36,38 or these models concentrate on preterm brain development. 18,19,37 Chorioamnionitis represents a local, intrauterine infection and is unique from the clinical scenarios observed with systemic infections, such as pyelonephritis and pneumonia.…”

“…[14][15][16][17][18][19] Specifically, in animal models, it has been demonstrated that exposure to intrauterine inflammation in the preterm period is associated with (1) an increase in proinflammatory cytokines in the fetal brain; (2) white matter damage (WMD), and (3) neuronal injury. [14][15][16][17][18][19] However, in term gestations, the mechanisms of the associated neurobehavioral findings remain unknown. Despite the assumption that the term brain might be more resistant to injury, 20 epidemiologic studies indicate that chorioamnionitis at term has a higher rate of CP than in preterm infants.…”