Cell-free oxidized hemoglobin drives reactive oxygen species production and pro-inflammation in an immature primary rat mixed glial cell culture
Agyemang, Alex Adusei LU ; Kvist, Suvi Vallius LU ; Brinkman, Nathan ; Gentinetta, Thomas ; Illa, Miriam ; Ortenlöf, Niklas LU ; Holmqvist, Bo LU ; Ley, David LU and Gram, Magnus LU
(2021)
In Journal of Neuroinflammation
18(1).
- Abstract
BACKGROUND: Germinal matrix intraventricular hemorrhage (GM-IVH) is associated with deposition of redox active cell-free hemoglobin (Hb), derived from hemorrhagic cerebrospinal fluid (CSF), in the cerebrum and cerebellum. In a recent study, using a preterm rabbit pup model of IVH, intraventricularly administered haptoglobin (Hp), a cell-free Hb scavenger, partially reversed the damaging effects observed following IVH. Together, this suggests that cell-free Hb is central in the pathophysiology of the injury to the immature brain following GM-IVH. An increased understanding of the causal pathways and metabolites involved in eliciting the damaging response following hemorrhage is essential for the continued development and implementation... (More)
BACKGROUND: Germinal matrix intraventricular hemorrhage (GM-IVH) is associated with deposition of redox active cell-free hemoglobin (Hb), derived from hemorrhagic cerebrospinal fluid (CSF), in the cerebrum and cerebellum. In a recent study, using a preterm rabbit pup model of IVH, intraventricularly administered haptoglobin (Hp), a cell-free Hb scavenger, partially reversed the damaging effects observed following IVH. Together, this suggests that cell-free Hb is central in the pathophysiology of the injury to the immature brain following GM-IVH. An increased understanding of the causal pathways and metabolites involved in eliciting the damaging response following hemorrhage is essential for the continued development and implementation of neuroprotective treatments of GM-IVH in preterm infant.
METHODS: We exposed immature primary rat mixed glial cells to hemorrhagic CSF obtained from preterm human infants with IVH (containing a mixture of Hb-metabolites) or to a range of pure Hb-metabolites, incl. oxidized Hb (mainly metHb with iron in Fe3+), oxyHb (mainly Fe2+), or low equivalents of heme, with or without co-administration with human Hp (a mixture of isotype 2-2/2-1). Following exposure, cellular response, reactive oxygen species (ROS) generation, secretion and expression of pro-inflammatory cytokines and oxidative markers were evaluated.
RESULTS: Exposure of the glial cells to hemorrhagic CSF as well as oxidized Hb, but not oxyHb, resulted in a significantly increased rate of ROS production that positively correlated with the rate of production of pro-inflammatory and oxidative markers. Congruently, exposure to oxidized Hb caused a disintegration of the polygonal cytoskeletal structure of the glial cells in addition to upregulation of F-actin proteins in microglial cells. Co-administration of Hp partially reversed the damaging response of hemorrhagic CSF and oxidized Hb.
CONCLUSION: Exposure of mixed glial cells to oxidized Hb initiates a pro-inflammatory and oxidative response with cytoskeletal disintegration. Early administration of Hp, aiming to minimize the spontaneous autoxidation of cell-free oxyHb and liberation of heme, may provide a therapeutic benefit in preterm infant with GM-IVH.
(Less)
- author
- Agyemang, Alex Adusei
LU
; Kvist, Suvi Vallius
LU
; Brinkman, Nathan
; Gentinetta, Thomas
; Illa, Miriam
; Ortenlöf, Niklas
LU
; Holmqvist, Bo
LU
; Ley, David
LU
and Gram, Magnus
LU
- organization
- publishing date
- 2021-02-11
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Neuroinflammation
- volume
- 18
- issue
- 1
- article number
- 42
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:33573677
- scopus:85100749496
- ISSN
- 1742-2094
- DOI
- 10.1186/s12974-020-02052-4
- language
- English
- LU publication?
- yes
- id
- 1540ed64-49d3-4b24-a19e-5cc4a56eaa43
- date added to LUP
- 2021-02-15 18:40:24
- date last changed
- 2024-06-27 08:28:49
@article{1540ed64-49d3-4b24-a19e-5cc4a56eaa43,
abstract = {{<p>BACKGROUND: Germinal matrix intraventricular hemorrhage (GM-IVH) is associated with deposition of redox active cell-free hemoglobin (Hb), derived from hemorrhagic cerebrospinal fluid (CSF), in the cerebrum and cerebellum. In a recent study, using a preterm rabbit pup model of IVH, intraventricularly administered haptoglobin (Hp), a cell-free Hb scavenger, partially reversed the damaging effects observed following IVH. Together, this suggests that cell-free Hb is central in the pathophysiology of the injury to the immature brain following GM-IVH. An increased understanding of the causal pathways and metabolites involved in eliciting the damaging response following hemorrhage is essential for the continued development and implementation of neuroprotective treatments of GM-IVH in preterm infant.</p><p>METHODS: We exposed immature primary rat mixed glial cells to hemorrhagic CSF obtained from preterm human infants with IVH (containing a mixture of Hb-metabolites) or to a range of pure Hb-metabolites, incl. oxidized Hb (mainly metHb with iron in Fe3+), oxyHb (mainly Fe2+), or low equivalents of heme, with or without co-administration with human Hp (a mixture of isotype 2-2/2-1). Following exposure, cellular response, reactive oxygen species (ROS) generation, secretion and expression of pro-inflammatory cytokines and oxidative markers were evaluated.</p><p>RESULTS: Exposure of the glial cells to hemorrhagic CSF as well as oxidized Hb, but not oxyHb, resulted in a significantly increased rate of ROS production that positively correlated with the rate of production of pro-inflammatory and oxidative markers. Congruently, exposure to oxidized Hb caused a disintegration of the polygonal cytoskeletal structure of the glial cells in addition to upregulation of F-actin proteins in microglial cells. Co-administration of Hp partially reversed the damaging response of hemorrhagic CSF and oxidized Hb.</p><p>CONCLUSION: Exposure of mixed glial cells to oxidized Hb initiates a pro-inflammatory and oxidative response with cytoskeletal disintegration. Early administration of Hp, aiming to minimize the spontaneous autoxidation of cell-free oxyHb and liberation of heme, may provide a therapeutic benefit in preterm infant with GM-IVH.</p>}},
author = {{Agyemang, Alex Adusei and Kvist, Suvi Vallius and Brinkman, Nathan and Gentinetta, Thomas and Illa, Miriam and Ortenlöf, Niklas and Holmqvist, Bo and Ley, David and Gram, Magnus}},
issn = {{1742-2094}},
language = {{eng}},
month = {{02}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Journal of Neuroinflammation}},
title = {{Cell-free oxidized hemoglobin drives reactive oxygen species production and pro-inflammation in an immature primary rat mixed glial cell culture}},
url = {{http://dx.doi.org/10.1186/s12974-020-02052-4}},
doi = {{10.1186/s12974-020-02052-4}},
volume = {{18}},
year = {{2021}},
}