Chorioamnionitis Precipitates Perinatal Alterations of Heme-Oxygenase-1 (HO-1) Homeostasis in the Developing Rat Brain.

Maide Ozen,Yuma Kitase,Shenandoah Robinson,Lauren L Jantzie,Sindhu Ramachandra,Christopher Burkhardt,Vikram Vasan

doi:10.3390/ijms22115773

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.

Highlights

IntroductionIn human very low birth weight (VLBW) neonates, inflammation and hypoxia-ischemia result in a cumulative increase in the risk of cerebral palsy (CP) [1]
Perinatal infection and inflammation have central roles in adverse neurodevelopment.In human very low birth weight (VLBW) neonates, inflammation and hypoxia-ischemia result in a cumulative increase in the risk of cerebral palsy (CP) [1]
This study reports for the first time a loss of the normal developmental regulation of HO-1/transferrin receptor-1 (TfR1) in the developing central nervous system (CNS) after CHORIO using an established and translational model of CP

Summary

Introduction

In human very low birth weight (VLBW) neonates, inflammation and hypoxia-ischemia result in a cumulative increase in the risk of cerebral palsy (CP) [1]. Preterm neonates are at increased risk for motor and cognitive impairment of which the odds are exacerbated in the presence of exposure to chorioamnionitis [2,3]. The concept of intra-uterine sterile inflammation has been emphasized by a number of researchers in the etiopathogenesis of preterm labor and premature birth [4,5]. The inflammation of the chorioamnion, can extend to the villi (acute villitis), to umbilical cord (funisitis) and result in a systemic fetal inflammatory response syndrome (FIRS) [4]. Fetal inflammatory response syndrome type 1, with associated increases in amniotic fluid and fetal serum IL-6, is associated with acute chorioamnionitis [5]. FIRS is an independent predictor of neonatal morbidity, and significantly increases the risk of periventricular leukomalacia (PVL) and

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