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Updated: May 16, 2026
A Ferret Model of Inflammation-sensitized Late Preterm Hypoxic-ischemic Brain Injury
Published on: November 19, 2019
Interaction of inflammation and hyperoxia in a rat model of neonatal white matter damage
Felix Brehmer1, Ivo Bendix, Sebastian Prager
1Department of Neonatology, Charité University Medical Center, Berlin, Germany. felix.brehmer@charite.de
Insights
Systemic lipopolysaccharide (LPS) and hyperoxia, common in preterm infants, cause white matter damage. LPS pre-incubation protected developing oligodendrocytes from hyperoxia in vitro, suggesting a potential therapeutic mechanism.
Area of Science:
- Neuroscience
- Developmental Biology
- Neonatal Medicine
Background:
- Intrauterine infection/inflammation and hyperoxia are key factors in preterm birth complications.
- Both conditions are implicated in white matter damage (WMD) in preterm infants.
- Their combined effects on WMD are not fully understood.
Purpose of the Study:
- To investigate the additive or synergistic effects of lipopolysaccharide (LPS)-induced inflammation and hyperoxia on white matter damage in newborn rats.
- To explore the underlying cellular mechanisms and potential protective effects of LPS.
Main Methods:
- Newborn Wistar rats were treated with LPS and exposed to hyperoxia.
- White matter damage was assessed using immunohistochemistry, Western blots, and diffusion tensor MRI.
- In vitro co-cultures of oligodendrocytes and microglia were used to study cellular responses.
Main Results:
- Both LPS and hyperoxia independently caused hypomyelination and white matter microstructure alterations.
- Hyperoxia induced oligodendrocyte cell death, while LPS caused maturity arrest without cell death.
- LPS pre-incubation reduced oligodendrocyte susceptibility to hyperoxia in vitro, potentially via IL-10 and SOD upregulation.
Conclusions:
- LPS and hyperoxia have distinct effects on oligodendrocyte development and WMD.
- LPS may offer a protective effect against hyperoxia-induced WMD by preventing cell death and promoting maturity.
- Understanding these mechanisms is crucial for developing strategies to prevent WMD in premature infants.
Abstract:
Intrauterine infection and inflammation are major reasons for preterm birth. The switch from placenta-mediated to lung-mediated oxygen supply during birth is associated with a sudden rise of tissue oxygen tension that amounts to relative hyperoxia in preterm infants. Both infection/inflammation and hyperoxia have been shown to be involved in brain injury of preterm infants. Hypothesizing that they might be additive or synergistic, we investigated the influence of a systemic lipopolysaccharide (LPS) application on hyperoxia-induced white matter damage (WMD) in newborn rats. Three-day-old Wistar rat pups received 0.25 mg/kg LPS i.p. and were subjected to 80% oxygen on P6 for 24 h. The extent of WMD was assessed by immunohistochemistry, western blots, and diffusion tensor (DT) magnetic resonance imaging (MRI). In addition, the effects of LPS and hyperoxia were studied in an in vitro co-culture system of primary rat oligodendrocytes and microglia cells. Both noxious stimuli, hyperoxia, and LPS caused hypomyelination as revealed by western blot, immunohistochemistry, and altered WM microstructure on DT-MRI. Even so, cellular changes resulting in hypomyelination seem to be different. While hyperoxia induces cell death, LPS induces oligodendrocyte maturity arrest without cell death as revealed by TUNEL-staining and immunohistological maturation analysis. In the two-hit scenario cell death is reduced compared with hyperoxia treated animals, nevertheless white matter alterations persist. Concordantly with these in vivo findings we demonstrate that LPS pre-incubation reduced premyelinating-oligodendrocyte susceptibility towards hyperoxia in vitro. This protective effect might be caused by upregulation of interleukin-10 and superoxide dismutase expression after LPS stimulation. Reduced expression of transcription factors controlling oligodendrocyte development and maturation further indicates oligodendrocyte maturity arrest. The knowledge about mechanisms that triggered hypomyelination contributes to a better understanding of WMD in premature born infants.
