BackgroundIn very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. Microglia and microvascular endothelial cells closely interact; therefore, a common signaling pathway may cause neuroinflammation and blood–brain barrier (BBB) damage after injury to the immature brain. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. CXCL5 levels markedly increased in the amniotic cavity in response to intrauterine infection and preterm birth in clinical studies. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain.MethodsPostpartum day 2 (P2) rat pups received lipopolysaccharide (LPS) followed by 90-min HI. Immunohistochemical analyses were performed to determine microglial activation, neutrophil infiltration, BBB damage, and myelin basic protein and glial fibrillary acidic protein expression. Immunofluorescence experiments were performed to determine the cellular distribution of CXCL5. Pharmacological tests were performed to inhibit or enhance CXCL5 activity.ResultsOn P2, predominant increases in microglial activation and BBB damage were observed 24 h after LPS-sensitized HI induction, and white matter injury (decreased myelination and increased astrogliosis) was observed on P12 compared with controls. Immunohistochemical analyses revealed increased CXCL5 expression in the white matter 6 and 24 h after insult. Immunofluorescence experiments revealed upregulated CXCL5 expression in the activated microglia and endothelial cells 24 h after insult. CXCL5 inhibition by SB225002, a selective nonpeptide inhibitor of CXCR2, significantly attenuated microglial activation and BBB damage, increased myelination, and reduced astrogliosis in the white matter after LPS-sensitized HI. In addition, CXCL5-sensitized HI or CXCL5 alone significantly induced BBB damage and white matter injury in association with different neuroinflammation mechanisms. CXCL5-sensitized HI-induced microglial activation and neutrophil infiltration, whereas CXCL5 alone predominately caused neutrophil infiltration.ConclusionsCXCL5 is a potential biomarker for white matter injury in preterm infants. Pharmacological blockade of CXCL5 signaling that attenuates dysregulated neuroinflammation can be used a therapeutic strategy against white matter injury in the immature brain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0474-6) contains supplementary material, which is available to authorized users.

Low birth weight is a major risk factor for ROP. Infants with extremely low birth weight had a higher risk of severe ROP. Common ocular sequelae of advanced ROP were myopia and anisometropia.

Microvascular injury early after hypoxic ischemia (HI) may contribute to neonatal brain damage. N-methyl-D-aspartate receptor overstimulation activates neuronal nitric oxide synthases (nNOS). We hypothesized that microvascular damage occurs early post-HI via nNOS activation and contributes to brain injury. Postpartum day-7 rat pups were treated with 7-nitroindazole (7-NI) or aminoguanidine (AG) before or after HI. Electron microscopy was performed to measure neuronal and endothelial cell damage. There were vascular lumen narrowing at 1 hour, pyknotic neurons at 3 hours, and extensive neuronal damage and loss of vessels at 24 hours post HI. Early after reoxygenation, there were neurons with heterochromatic chromatin and endothelial cells with enlarged nuclei occluding the lumen. There was also increased 3-nitrotyrosin in the microvessels and decreased cerebral blood perfusion. 7-NI and AG treatment before hypoxia provided complete and partial neuroprotection, respectively. Early post-reoxygenation, the AG group showed significantly increased microvascular nitrosative stress, microvascular interruptions, swollen nuclei that narrowed the vascular lumen, and decreased cerebral perfusion. The 7-NI group showed significantly decreased microvascular nitrosative stress, patent vascular lumen, and increased cerebral perfusion. Our results indicate that microvascular damage occurs early and progressively post HI. Neuronal nitric oxide synthases activation contributes to microvascular damage and decreased cerebral perfusion early after reoxygenation and worsens brain damage.

Background. Dexamethasone (Dex) has been used to reduce inflammation in preterm infants with assistive ventilation and to prevent chronic lung diseases. However, Dex treatment results in adverse effects on the brain. Since the hippocampus contains a high density of glucocorticoid receptors (GCRs), we hypothesized that Dex affects neurogenesis in the hippocampus through inflammatory mediators. Methods. Albino Wistar rat pups first received a single dose of Dex (0.5 mg/kg) on postnatal day 1 (P1) and were sacrificed on P2, P3, P5, and P7. One group of Dex-treated pups (Dex-treated D1D2) was given mifepristone (RU486, a GCR antagonist) on P1 and sacrificed on P2. Hippocampi were isolated for western blot analysis, TUNEL, cleaved-caspase 3 staining for cell counts, and morphological assessment. Control pups received normal saline (NS). Results. Dex reduced the developmental gain in body weight, but had no effect on brain weight. In the Dex-treated D1D2 group, apoptotic cells increased in number based on TUNEL and cleaved-caspase 3 staining. Most of the apoptotic cells expressed the neural progenitor cell marker nestin. Dex-induced apoptosis in P1 pups was markedly reduced (60%) by pretreatment with RU486, indicating the involvement of GCRs. Conclusion. Early administration of Dex results in apoptosis of neural progenitor cells in the hippocampus and this is mediated through GCRs.

Background: Cystic periventricular leukomalacia (cPVL) is the most severe white matter injury and is often associated with intraventricular hemorrhage (IVH) in preterm infants. Objective: The aim of this study was to investigate the prevalence, risk factors and neurodevelopmental outcomes of isolated cPVL and cPVL with low-grade and high-grade IVH in premature infants. Methods: From 2001 to 2012, 9,964 infants with <31 weeks' gestational age (GA) admitted to Taiwan hospitals were enrolled. cPVL was classified into three groups: isolated cPVL, cPVL with low-grade (I/II) IVH, and cPVL with high-grade (III) IVH. Results: Of 7,805 infants with complete ultrasound data, 286 (3.7%) had cPVL. Among the cPVL infants, 93 (32.5%) were isolated, 118 (41.3%) had low-grade IVH and 75 (26.2%) had high-grade IVH. The risk of cPVL with IVH was significantly higher among infants with <27 weeks' GA than those with ≥27 weeks' GA, in contrast to that of isolated cPVL. Using infants without cPVL and IVH as the reference group, the most significant predictor of isolated cPVL was neonatal sepsis (odds ratio 2.39; 95% confidence interval 1.52-3.77), while 5-min Apgar score <5 (2.50; 1.48-4.21) and prolonged mechanical ventilation (2.19; 1.42-3.42) were associated with cPVL with low-grade IVH, and GA <27 weeks (2.63; 1.56-4.42), pneumothorax (3.04; 1.40-6.65) and prolonged mechanical ventilation (3.36; 1.88-6.01) contributed to cPVL with high-grade IVH. cPVL infants with low-grade and high-grade IVH had a higher risk of abnormal neurodevelopmental outcomes than infants with isolated cPVL at the age of 24 months. Conclusions: Isolated cPVL, cPVL with low-grade IVH and cPVL with high-grade IVH had different risk factors and neurodevelopmental outcomes, suggestive of different causal pathways.