Chorioamnionitis-induced perinatal alterations of Heme-oxygenase-1 (HO-1) pathway in the developing rat brain correlate with neuroinflammation at term equivalent age

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Background: 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/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. HO-1 is a major immune regulator. However, the role of HO in the pathophysiology of PBI has not been previously studied. 

Objective: To determine if CHORIO-induced alterations of HO-1 pathway in the brain results in neuroinflammation in a clinically relevant rat model of PBI. 

Design/Methods: Pregnant Sprague-Dawley rats were stratified to Sham or CHORIO groups and underwent laparotomy on embryonic day 18 (E18). CHORIO was induced by transient occlusion of the uterine arteries followed by intra-amniotic injection of lipopolysaccharide (LPS, 4 μg/sac). Shams received laparotomy with equivalent duration of anesthesia. Brains were collected at E18+6h, E19 and postnatal day (P) 2, HO-1, HO-2 and TfR1 mRNA expression was measured by qPCR. Brain mononuclear cells were studied at P7 by flow cytometry. Constitutive HO (HO-2) was measured to show the specificity of HO-1 and TfR1 changes. n=3-10. Data are represented as mean±SEM. p<0.05 considered significant. 

Results: HO-1, HO-2 and TfR1 expression were developmentally regulated and increased from E18+6h to P2 (p<0.05 for all). CHORIO altered the developmental expression of HO-1 and TfR1 mRNA. At E18+6h after CHORIO, HO-1/HO-2 (4.1) and HO-1/TfR1 ratios (3.7) were altered in favor of excess HO-1, in fetal brains compared with Sham. HO-1/HO-2 ratios were similar. In contrast, HO-1/TfR1 ratios remained elevated at E19 (1.1) and at P2 (1.1) compared with Sham (0.6, and 0.4, respectively). This was followed by a significant increase in the CD45+CD11b/c+ mononuclear cells in CHORIO brains (10.0±1.514) at P7 compared with Sham (4.71±0.3649, p=0.0098). 

Conclusion(s): CHORIO elevates HO-1 and TfR1 mRNA expression in utero and in the early perinatal period and results in a sustained increase in HO-1/TfR1 ratios. This is accompanied by  increased neuroinflammation at term equivalent age with increased CD45+CD11b/c+ cells. Because discrete regulation of HO-1, HO-2 and TfR1 is important for homeostatic ontogeny and may be fundamental to neurodevelopment, more studies are needed to define the consequences of altered HO-1 signaling in neuroinflammation in CHORIO. 

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