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Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus
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 infe...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907370/ https://www.ncbi.nlm.nih.gov/pubmed/29673373 http://dx.doi.org/10.1186/s12974-018-1149-x |
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author | Gussenhoven, Ruth Westerlaken, Rob J. J. Ophelders, Daan R. M. G. Jobe, Alan H. Kemp, Matthew W. Kallapur, Suhas G. Zimmermann, Luc J. Sangild, Per T. Pankratova, Stanislava Gressens, Pierre Kramer, Boris W. Fleiss, Bobbi Wolfs, Tim G. A. M. |
author_facet | Gussenhoven, Ruth Westerlaken, Rob J. J. Ophelders, Daan R. M. G. Jobe, Alan H. Kemp, Matthew W. Kallapur, Suhas G. Zimmermann, Luc J. Sangild, Per T. Pankratova, Stanislava Gressens, Pierre Kramer, Boris W. Fleiss, Bobbi Wolfs, Tim G. A. M. |
author_sort | Gussenhoven, Ruth |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5907370 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-59073702018-04-30 Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus Gussenhoven, Ruth Westerlaken, Rob J. J. Ophelders, Daan R. M. G. Jobe, Alan H. Kemp, Matthew W. Kallapur, Suhas G. Zimmermann, Luc J. Sangild, Per T. Pankratova, Stanislava Gressens, Pierre Kramer, Boris W. Fleiss, Bobbi Wolfs, Tim G. A. M. J Neuroinflammation Research 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. BioMed Central 2018-04-19 /pmc/articles/PMC5907370/ /pubmed/29673373 http://dx.doi.org/10.1186/s12974-018-1149-x Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Gussenhoven, Ruth Westerlaken, Rob J. J. Ophelders, Daan R. M. G. Jobe, Alan H. Kemp, Matthew W. Kallapur, Suhas G. Zimmermann, Luc J. Sangild, Per T. Pankratova, Stanislava Gressens, Pierre Kramer, Boris W. Fleiss, Bobbi Wolfs, Tim G. A. M. Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus |
title | Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus |
title_full | Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus |
title_fullStr | Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus |
title_full_unstemmed | Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus |
title_short | Chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus |
title_sort | chorioamnionitis, neuroinflammation, and injury: timing is key in the preterm ovine fetus |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907370/ https://www.ncbi.nlm.nih.gov/pubmed/29673373 http://dx.doi.org/10.1186/s12974-018-1149-x |
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