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Open Access 01-12-2018 | Research

Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus

Authors: Ruth Gussenhoven, Rob J. J. Westerlaken, Daan R. M. G. Ophelders, Alan H. Jobe, Matthew W. Kemp, Suhas G. Kallapur, Luc J. Zimmermann, Per T. Sangild, Stanislava Pankratova, Pierre Gressens, Boris W. Kramer, Bobbi Fleiss, Tim G. A. M. Wolfs

Published in: Journal of Neuroinflammation | Issue 1/2018

Abstract

Background

Antenatal infection (i.e., chorioamnionitis) is an important risk factor for adverse neurodevelopmental outcomes after preterm birth. Destructive and developmental disturbances of the white matter are hallmarks of preterm brain injury. Understanding the temporal effects of antenatal infection in relation to the onset of neurological injury is crucial for the development of neurotherapeutics for preterm infants. However, these dynamics remain unstudied.

Methods

Time-mated ewes were intra-amniotically injected with lipopolysaccharide at 5, 12, or 24 h or 2, 4, 8, or 15 days before preterm delivery at 125 days gestational age (term ~ 150 days). Post mortem analyses for peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed. Moreover, considering the neuroprotective potential of erythropoietin (EPO) for perinatal brain injury, we evaluated (phosphorylated) EPO receptor (pEPOR) expression in the fetal brain following LPS exposure.

Results

Intra-amniotic exposure to this single bolus of LPS resulted in a biphasic systemic IL-6 and IL-8 response. In the developing brain, intra-amniotic LPS exposure induces a persistent microgliosis (IBA-1 immunoreactivity) but a shorter-lived increase in the pro-inflammatory marker COX-2. Cell death (caspase-3 immunoreactivity) was only observed when LPS exposure was greater than 8 days in the white matter, and there was a reduction in the number of (pre) oligodendrocytes (Olig2- and PDGFRα-positive cells) within the white matter at 15 days post LPS exposure only. pEPOR expression displayed a striking biphasic regulation following LPS exposure which may help explain contradicting results among clinical trials that tested EPO for the prevention of preterm brain injury.

Conclusion

We provide increased understanding of the spatiotemporal pathophysiological changes in the preterm brain following intra-amniotic inflammation which may aid development of new interventions or implement interventions more effectively to prevent perinatal brain damage.

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Title: Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus
Authors: Ruth Gussenhoven
Rob J. J. Westerlaken
Daan R. M. G. Ophelders
Alan H. Jobe
Matthew W. Kemp
Suhas G. Kallapur
Luc J. Zimmermann
Per T. Sangild
Stanislava Pankratova
Pierre Gressens
Boris W. Kramer
Bobbi Fleiss
Tim G. A. M. Wolfs
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-018-1149-x

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus

Abstract

Background

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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