Preterm birth can be caused by intrauterine infection and maternal/fetal inflammatory responses. Maternal inflammation (chorioamnionitis) is often followed by a systemic fetal inflammatory response characterized by elevated levels of pro-inflammatory cytokines in the fetal circulation. The inflammation signal is likely transmitted across the blood-brain barrier, and initiates a neuroinflammatory response. Microglial activation has a central role in this process, and triggers excitotoxic, inflammatory, and oxidative damage in the developing brain. Neuroinflammation can persist over a period of time and sensitize the brain to subinjurious insults in early and chronic phases, but may offer relative tolerance in the intermediate period through activation of endogenous anti-inflammatory, protective, and repair mechanisms. Neuroinflammatory injury not only destroys what exists, but also changes what develops.

Sadowska GB, Malaeb SN, Stonestreet BS. Maternal glucocorticoid exposure alters tight junction protein expression in the brain of fetal sheep. Am J Physiol Heart Circ Physiol 298: H179 -H188, 2010. First published October 23, 2009 doi:10.1152/ajpheart.00828.2009.-We examined the expression of tight junction (TJ) proteins in the cerebral cortex, cerebellum, and spinal cord of fetuses after maternal treatment with single and multiple courses of dexamethasone. Ewes received either single courses of four 6-mg dexamethasone or placebo injections every 12 h for 48 h between 104 and 107 days or the same treatment once a week between 76 -78 and 104 -107 days of gestation. TJ protein expression was determined by Western immunoblot analysis on tissue harvested at 105-108 days of gestation. Blood-brain barrier permeability has been previously quantified with the blood-tobrain transfer constant (K i) with ␣-aminoisobutyric acid (39). After a single course of dexamethasone, claudin-5 increased (P Ͻ 0.05) in the cerebral cortex, occludin and claudin-1 increased in the cerebellum, and occludin increased in the spinal cord. After multiple dexamethasone courses, occludin and zonula occludens (ZO)-1 increased in the cerebral cortex, and occludin and claudin-1 increased in the cerebellum. Junctional adhesion molecule-A and ZO-2 expressions did not change. Linear regression comparing K i to TJ proteins showed inverse correlations with claudin-1 and claudin-5 in the cerebral cortex after a single course and ZO-2 in the spinal cord after multiple courses and direct correlations with ZO-1 in the cerebellum and spinal cord after multiple courses. We conclude that maternal glucocorticoid treatment increases the expression of specific TJ proteins in vivo, patterns of TJ protein expression vary after exposure to single and multiple glucocorticoid courses, and decreases in blood-brain barrier permeability are associated with increases in claudin-1, claudin-5, and ZO-2 expression and decreases in ZO-1 expression. In utero glucocorticoid exposure alters the molecular composition of the barrier and affects fetal blood-brain barrier function.blood-brain barrier; dexamethasone; steroids THE BLOOD-BRAIN BARRIER is composed of a continuous layer of cerebrovascular endothelial cells connected by intercellular tight junctions (TJs) (4). TJs are composed of transmembrane and associated cytoplasmic proteins (22). The transmembrane proteins include occludin, claudins, and junctional adhesion molecules (JAMs). The proteins of the claudin family form the primary seal between adjacent endothelial cells, whereas occludin is an important support molecule that increases electrical resistance across the barrier and decreases paracellular permeability (22). JAMs regulate TJ formation and leukocyte and endothelial cell interactions (13). The associated cytoplasmic proteins zonula occuldens (ZO)-1 and ZO-2 stabilize TJs by connecting them to actin (22).Maternally administered glucocorticoids have been widely used to accelerate fetal maturation (9,12,30,34). Th...

Maternal treatment with corticosteroids reduces blood-brain barrier permeability in premature ovine fetuses and the incidence of intraventricular hemorrhage in premature infants. We tested the hypothesis that maternally administered corticosteroids increase the expression of tight junction (TJ) proteins in the cerebral cortex of ovine fetuses with and without exposure to in utero brain ischemia. Fetuses at 80% of gestation were studied 18 h after the last of four 4-6 mg dexamethasone or placebo injections were given over 48 h to ewes. Groups were placebo/control, dexamethasone/control, placebo/ischemic, and dexamethasone/ischemic. Ischemia consisted of 30 min of fetal carotid artery occlusion and 72 h of reperfusion. Cerebral cortex was snap frozen. Western immunoblot was used to measure the protein expression of occludin, claudin-1, claudin-5, zonula occludens (ZO)-1, and ZO-2, and a TJ accessory protein annexin-ll. Occludin and annexin-ll protein expression were 48% and 58% higher (P<0.05) in the dexamethasone/ischemic than placebo/control group, respectively. Claudin-5 protein expression was 69% and 73% higher (P<0.05) in the placebo/ischemic and dexamethasone/ischemic than placebo/control group. Claudin-1 expression did not differ among groups. ZO-1 protein expression was 25%, 40%, and 55% lower in the dexamethasone/control, placebo/ischemic, and dexamethasone/ischemic than placebo/control group, respectively. ZO-2 expression was 45% and 70% lower (P<0.01) in the placebo/ischemic and dexamethasone/ischemic than placebo/control group. We conclude that maternal corticosteroid treatment differentially regulates the expression of component proteins of TJs in the cerebral cortex of fetuses exposed to brain ischemia. The functional significance of this differential regulation warrants further investigation.