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Extracellular hemoglobin - mediator of inflammation and cell death in the choroid plexus following preterm intraventricular hemorrhage

Gram, Magnus LU ; Sveinsdottir, Snjolaug LU ; Cinthio, Magnus LU ; Sveinsdottir, Kristbjörg LU ; Hansson, Stefan LU ; Mörgelin, Matthias LU ; Åkerström, Bo LU and Ley, David LU (2014) In Journal of Neuroinflammation 11.
Abstract
Background: Intraventricular hemorrhage (IVH) with post-hemorrhagic ventricular dilatation (PHVD) is a major cause of neurodevelopmental impairment and mortality in preterm infants. The mechanisms leading to PHVD and brain damage remain largely unknown. The choroid plexus and the ependyma, which constitute an essential part of the blood-brain barrier (BBB), are the first structures to encounter the damaging effects of extravasated blood. The breakdown of the BBB is a critical upstream event leading to brain damage following IVH. In this study we investigated the impact of hemorrhage and hemoglobin (Hb) metabolites on the choroid plexus epithelium. Methods: Using a preterm rabbit pup model of IVH, the structural and functional integrity,... (More)
Background: Intraventricular hemorrhage (IVH) with post-hemorrhagic ventricular dilatation (PHVD) is a major cause of neurodevelopmental impairment and mortality in preterm infants. The mechanisms leading to PHVD and brain damage remain largely unknown. The choroid plexus and the ependyma, which constitute an essential part of the blood-brain barrier (BBB), are the first structures to encounter the damaging effects of extravasated blood. The breakdown of the BBB is a critical upstream event leading to brain damage following IVH. In this study we investigated the impact of hemorrhage and hemoglobin (Hb) metabolites on the choroid plexus epithelium. Methods: Using a preterm rabbit pup model of IVH, the structural and functional integrity, cellular, inflammatory and oxidative response of the choroid plexus, at 24 and 72 hours following IVH + PHVD, were investigated. In order to further characterize cellular and molecular mechanisms, primary human choroid plexus epithelial cells were exposed to cerebrospinal fluid (CSF) from preterm infants with IVH as well as to Hb-metabolites. Finally, the blocking effects of the Hb-scavenger haptoglobin (Hp) were investigated both in vivo and in vitro. Results: Following IVH + PHVD, an up-regulation of mRNA for the receptor-related genes TLR-4, IL1R1, FAS, the transcription factor NF-kappa beta and for the pro-inflammatory and chemotactic effector molecules, IL-1 beta, TNF alpha, MCP-1, IL-8, and IL-6 was observed in the choroid plexus at 24 and 72 hours. This was associated with structural disintegration, caspase activation and cell death in the choroid plexus epithelium. In vitro characterization of choroid plexus epithelial cells, following exposure to hemorrhagic CSF and to the Hb-metabolites metHb and heme, displayed apoptotic and necrotic cell death and an up-regulation of receptor-related and inflammatory effector molecules similar to that observed in vivo following IVH + PHVD. Intraventricular injection of the Hb-scavenger Hp in vivo and co-incubation with Hp in vitro reversed or reduced the cellular activation, inflammatory response, structural damage and cell death. Conclusion: Hb-metabolites are important causal initiators of cell death following IVH and removal or scavenging of Hb-metabolites may present an efficient means to reduce the damage to the immature brain following IVH. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Intraventricular hemorrhage, Post-hemorrhagic hydrocephalus, Preterm, birth, Choroid plexus, Epithelial cells, Inflammation, Tissue damage, Cell death, Hemoglobin, Haptoglobin
in
Journal of Neuroinflammation
volume
11
publisher
BioMed Central
external identifiers
  • wos:000347116200001
  • scopus:84924917774
ISSN
1742-2094
DOI
10.1186/s12974-014-0200-9
language
English
LU publication?
yes
id
f7d743ac-5e17-48d5-883d-6d9ef9c91466 (old id 5085352)
date added to LUP
2015-02-26 15:30:39
date last changed
2017-11-19 03:54:10
@article{f7d743ac-5e17-48d5-883d-6d9ef9c91466,
  abstract     = {Background: Intraventricular hemorrhage (IVH) with post-hemorrhagic ventricular dilatation (PHVD) is a major cause of neurodevelopmental impairment and mortality in preterm infants. The mechanisms leading to PHVD and brain damage remain largely unknown. The choroid plexus and the ependyma, which constitute an essential part of the blood-brain barrier (BBB), are the first structures to encounter the damaging effects of extravasated blood. The breakdown of the BBB is a critical upstream event leading to brain damage following IVH. In this study we investigated the impact of hemorrhage and hemoglobin (Hb) metabolites on the choroid plexus epithelium. Methods: Using a preterm rabbit pup model of IVH, the structural and functional integrity, cellular, inflammatory and oxidative response of the choroid plexus, at 24 and 72 hours following IVH + PHVD, were investigated. In order to further characterize cellular and molecular mechanisms, primary human choroid plexus epithelial cells were exposed to cerebrospinal fluid (CSF) from preterm infants with IVH as well as to Hb-metabolites. Finally, the blocking effects of the Hb-scavenger haptoglobin (Hp) were investigated both in vivo and in vitro. Results: Following IVH + PHVD, an up-regulation of mRNA for the receptor-related genes TLR-4, IL1R1, FAS, the transcription factor NF-kappa beta and for the pro-inflammatory and chemotactic effector molecules, IL-1 beta, TNF alpha, MCP-1, IL-8, and IL-6 was observed in the choroid plexus at 24 and 72 hours. This was associated with structural disintegration, caspase activation and cell death in the choroid plexus epithelium. In vitro characterization of choroid plexus epithelial cells, following exposure to hemorrhagic CSF and to the Hb-metabolites metHb and heme, displayed apoptotic and necrotic cell death and an up-regulation of receptor-related and inflammatory effector molecules similar to that observed in vivo following IVH + PHVD. Intraventricular injection of the Hb-scavenger Hp in vivo and co-incubation with Hp in vitro reversed or reduced the cellular activation, inflammatory response, structural damage and cell death. Conclusion: Hb-metabolites are important causal initiators of cell death following IVH and removal or scavenging of Hb-metabolites may present an efficient means to reduce the damage to the immature brain following IVH.},
  articleno    = {200},
  author       = {Gram, Magnus and Sveinsdottir, Snjolaug and Cinthio, Magnus and Sveinsdottir, Kristbjörg and Hansson, Stefan and Mörgelin, Matthias and Åkerström, Bo and Ley, David},
  issn         = {1742-2094},
  keyword      = {Intraventricular hemorrhage,Post-hemorrhagic hydrocephalus,Preterm,birth,Choroid plexus,Epithelial cells,Inflammation,Tissue damage,Cell death,Hemoglobin,Haptoglobin},
  language     = {eng},
  publisher    = {BioMed Central},
  series       = {Journal of Neuroinflammation},
  title        = {Extracellular hemoglobin - mediator of inflammation and cell death in the choroid plexus following preterm intraventricular hemorrhage},
  url          = {http://dx.doi.org/10.1186/s12974-014-0200-9},
  volume       = {11},
  year         = {2014},
}