Hypoxic-Ischaemic Encephalopathy and the Blood-Brain Barrier in Neonates

Lee, Wei Ling Amelia; Michael‐Titus, Adina T.; Shah, Divyen K.

doi:10.1159/000467392

Cited by 52 publications

(50 citation statements)

References 99 publications

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“…Endothelial hyperpermeability is specifically caused by cell junction breakdown, which ultimately leads to the formation of intracellular gaps [19]. Endothelial tight junctions are composed of the tetraspan transmembrane proteins claudin and occludin, the latter of which maintains the integrity of the endothelium in the blood-brain barrier [20]. Adherens junctions maintain the mechanical strength of intracellular adhesion by homophilic Ca…”

Section: At III Knockdown Impairs Endothelial Integritymentioning

confidence: 99%

ITRAQ-Based Proteomics Analysis of Acute Lung Injury Induced by Oleic Acid in Mice

Zhu

Zhang

et al. 2017

Cell Physiol Biochem

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Background/Aims: This study was conducted to investigate the relationship between differentially expressed proteins (DEPs) and the pathogenesis of oleic acid (OA)-induced acute lung injury (ALI) in mice. Methods: Eight-week-old male C57BL/6 mice were injected with OA through the tail vein and sacrificed 6 hours after OA administration to identify protein expression levels in lung tissue using isobaric tags for relative and absolute quantification (iTRAQ) technology. Then, DEPs such as antithrombin III (AT III), 12-lipoxygenase (12-LO), dedicator of cytokinesis 2 (DOCK2), polycystin-2 and plasminogen were identified by western blotting. Subsequently, we focused on investigating the effect of AT III on endothelial integrity using siRNA interference technology. The levels of IL-6, IL-1β, TNF-α and TGF-β expression were detected using an enzyme-linked immunosorbent assay (ELISA). Alterations in the tight junction component ZO-1 and the phosphorylation of myosin light chain (pMLC) were determined by western blotting. The stress fiber F-actin were also detected by immunofluorescence staining. In addition, endothelial permeability was determined via a transwell permeability assay. Results: A total of 5152 proteins were found to be expressed in lung tissues from the OA-treated and saline-treated mice. Among these proteins, 849 were differentially expressed between the two groups, including 545 upregulated and 304 downregulated proteins. After AT III knockdown, the levels of inflammatory factors and endothelial permeability were elevated, the expression of ZO-1 was decreased, and the expression of F-actin and pMLC was increased. All these results illustrated that AT III knockdown exaggerated the disruption of endothelial integrity mediated by OA. Conclusion: These findings using iTRAQ technology demonstrate, for the first time, differences in the lung tissue expression levels of proteins between OA-treated mice and saline-treated mice. This study reveals that 12-LO, DOCK2 and especially AT III may be candidate biomarkers for OA-induced acute lung injury.

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Section: At III Knockdown Impairs Endothelial Integritymentioning

confidence: 99%

ITRAQ-Based Proteomics Analysis of Acute Lung Injury Induced by Oleic Acid in Mice

Zhu

Zhang

et al. 2017

Cell Physiol Biochem

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“…At the BBB level, barrier function is dynamic and responsive to fluctuations in the circulation [10]. Disturbances in BBB function have been implicated in preterm and neonatal complications, such as hypoxic-ischemic or inflammation-related brain injury [11, 12]. Reduced astrocyte perivascular coverage, a late-stage BBB maturational process, has been reported in preterm infants and may impair brain vessel integrity and nutrient transfer [13].…”

Section: Introductionmentioning

confidence: 99%

Brain Barrier Disruption and Region-Specific Neuronal Degeneration during Necrotizing Enterocolitis in Preterm Pigs

2018

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Necrotizing enterocolitis (NEC) increases the risk of brain injury and impaired neurodevelopment. Rapid brain maturation prior to birth may explain why preterm brains are particularly vulnerable to serious infections. Using pigs as models, we hypothesized that preterm birth was associated with altered blood-cerebrospinal fluid (CSF) barrier (BCSFB) function and cerebral structural deficits, and that NEC was associated with systemic inflammation, BCSFB disruption, and neuroinflammation. First, cesarean-delivered preterm and term pigs (n = 43–44) were euthanized at birth to investigate BCSFB function and markers of brain structural maturation, or on day 5 to measure markers of blood-brain barrier maturation in the hippocampus and striatum (experiment 1). Next, preterm pigs (n = 162) were fed increasing volumes of infant formula to assess NEC lesions, systemic inflammation, BCSFB permeability, cerebral histopathology, hippocampal microglial density, and cytokine levels on day 5 (experiments 2 and 3). In experiment 1, preterm newborns had increased CSF-plasma ratios of albumin and raffinose, reduced CSF glucose levels, as well as increased cerebral hydration and reduced white matter myelination compared with term animals. We observed lower hippocampal (but not striatal) perivascular astrocyte coverage for the first 5 days after preterm birth, accompanied by altered cell junction protein levels. In experiments 2 and– 3, piglets with severe NEC lesions showed reduced blood thrombocytes and increased plasma C-reactive protein and interleukin-6 levels. NEC was associated with increased CSF-plasma albumin and raffinose ratios, reduced CSF leukocyte numbers, and increased cerebral hydration. In the hippocampus, NEC was associated with pyramidal neuron loss and increased interleukin-6 levels. In the short term, NEC did not affect cerebral myelination or microglia density. In conclusion, altered BCSFB properties and brain structural deficits were observed in pigs after preterm birth. Acute gastrointestinal NEC lesions were associated with systemic inflammation, increased BCSFB permeability and region-specific neuronal damage. The results demonstrate the importance of early interventions against NEC to prevent brain injury in preterm infants.

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“…Umbilical cord occlusion produced a significant reduction in vascular density in the caudate nucleus, and a trend toward reduction in the cortex (p = 0.08) and SCWM (p = 0.058); occlusion produced no significant alteration in vascular morphology in any region tested BBB, blood-brain barrier; CSF, cerebrospinal fluid; E (127), embryonic day (127); HI, hypoxia-ischemia; HIE, hypoxic-ischemic encephalopathy; KO, knockout; NMDA, N-methyl-D-aspartate; P (9), postnatal day (9); PVWM, periventricular white matter; SCWM, subcortical white matter; TJ, tight junction; WT, wild-type. Lee et al (2017) reviewed BBB permeability following neonatal HI insult, with studies reviewed using a variety of models and indicators of permeability, yet raising a number of shared conclusions. Among these was a general agreement that there exists an early increase in BBB permeability, peaking 2-4 h following the initial insult (Muramatsu et al, 1997;Chen et al, 2012;Ek et al, 2015;Lee et al, 2017).…”

Section: Authorsmentioning

confidence: 99%

“…Lee et al (2017) reviewed BBB permeability following neonatal HI insult, with studies reviewed using a variety of models and indicators of permeability, yet raising a number of shared conclusions. Among these was a general agreement that there exists an early increase in BBB permeability, peaking 2-4 h following the initial insult (Muramatsu et al, 1997;Chen et al, 2012;Ek et al, 2015;Lee et al, 2017). Interestingly, the review noted less support in these studies for a delayed second phase of increased BBB permeability, previously documented in adult models (Başkaya et al, 1997;Lee et al, 2017).…”

Section: Authorsmentioning

confidence: 99%

The Neurovascular Unit: Effects of Brain Insults During the Perinatal Period

et al. 2020

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The neurovascular unit (NVU) is a relatively recent concept in neuroscience that broadly describes the relationship between brain cells and their blood vessels. The NVU incorporates cellular and extracellular components involved in regulating cerebral blood flow and blood-brain barrier function. The NVU within the adult brain has attracted strong research interest and its structure and function is well described, however, the NVU in the developing brain over the fetal and neonatal period remains much less well known. One area of particular interest in perinatal brain development is the impact of known neuropathological insults on the NVU. The aim of this review is to synthesize existing literature to describe structure and function of the NVU in the developing brain, with a particular emphasis on exploring the effects of perinatal insults. Accordingly, a brief overview of NVU components and function is provided, before discussion of NVU development and how this may be affected by perinatal pathologies. We have focused this discussion around three common perinatal insults: prematurity, acute hypoxia, and chronic hypoxia. A greater understanding of processes affecting the NVU in the perinatal period may enable application of targeted therapies, as well as providing a useful basis for research as it expands further into this area.

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Hypoxic-Ischaemic Encephalopathy and the Blood-Brain Barrier in Neonates

Cited by 52 publications

References 99 publications

ITRAQ-Based Proteomics Analysis of Acute Lung Injury Induced by Oleic Acid in Mice

ITRAQ-Based Proteomics Analysis of Acute Lung Injury Induced by Oleic Acid in Mice

Brain Barrier Disruption and Region-Specific Neuronal Degeneration during Necrotizing Enterocolitis in Preterm Pigs

The Neurovascular Unit: Effects of Brain Insults During the Perinatal Period

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