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Updated: Nov 3, 2025
Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Chorioamnionitis Precipitates Perinatal Alterations of Heme-Oxygenase-1 (HO-1) Homeostasis in the Developing Rat
Maide Ozen1, Yuma Kitase1, Vikram Vasan1
1Department of Pediatrics, Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Insights
Chorioamnionitis elevates heme-oxygenase-1 (HO-1) and transferrin receptor-1 (TfR1) in the developing brain, contributing to neuroinflammation and perinatal brain injury. This pathway dysregulation is linked to altered immune cell populations.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Perinatal brain injury (PBI) is linked to chorioamnionitis (CHORIO), placental insufficiency, and preterm birth.
- Heme-oxygenase-1 (HO-1) and transferrin receptor-1 (TfR1) are critical for iron homeostasis and cellular responses to oxidative stress in the brain.
- The role of the HO pathway in PBI pathophysiology remains uninvestigated.
Purpose of the Study:
- To define the developmental regulation of the HO pathway in the brain.
- To investigate how CHORIO alters HO pathway ontogeny.
- To determine the role of HO-1/TfR1 in CHORIO-induced neuroinflammation and peripheral inflammation.
Main Methods:
- Utilized a clinically relevant rat model of PBI induced by CHORIO.
- Examined the ontogeny and developmental regulation of HO-1, HO-2, and TfR1 expression in the brain.
- Assessed changes in brain mononuclear cells and peripheral blood immune cells.
Main Results:
- HO-1, HO-2, and TfR1 expression are developmentally regulated in the perinatal brain.
- CHORIO significantly elevates HO-1 and TfR1 mRNA expression both in utero and postnatally.
- Sustained increases in brain HO-1/TfR1 ratios correlate with neuroinflammation and peripheral immune alterations, including increased brain mononuclear cells and peripheral double-negative T cells.
Conclusions:
- HO-1 and TfR1 expression are developmentally regulated in the perinatal brain.
- CHORIO disrupts this normal regulation, leading to elevated HO-1/TfR1 ratios.
- Dysregulation of the HO-1/TfR1 pathway contributes to CHORIO-induced neuroinflammation and associated immune changes, highlighting its role in PBI.
Abstract:
Chorioamnionitis (CHORIO), placental insufficiency, and preterm birth are well-known antecedents of perinatal brain injury (PBI). Heme-oxygenase-1 (HO-1) is an important inducible enzyme in oxidative and inflammatory conditions. In the brain, HO-1 and the iron regulatory receptor, transferrin receptor-1 (TfR1), are known to be involved in iron homeostasis, oxidative stress, and cellular adaptive mechanisms. However, the role of HO pathway in the pathophysiology of PBI has not been previously studied. In this study, we set out to define the ontogeny of the HO pathway in the brain and determine if CHORIO changed its normal developmental regulation. We also aimed to determine the role of HO-1/TfR1 in CHORIO-induced neuroinflammation and peripheral inflammation in a clinically relevant rat model of PBI. We show that HO-1, HO-2, and TfR1 expression are developmentally regulated in the brain during the perinatal period. CHORIO elevates HO-1 and TfR1 mRNA expression in utero and in the early postnatal period and results in sustained increase in HO-1/TfR1 ratios in the brain. This is associated with neuroinflammatory and peripheral immune phenotype supported by a significant increase in brain mononuclear cells and peripheral blood double negative T cells suggesting a role of HO-1/TfR1 pathway dysregulation in CHORIO-induced neuroinflammation.
