{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:24:31Z","timestamp":1792797871645,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01HL139492"],"award-info":[{"award-number":["1R01HL139492"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms22115773","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T11:33:20Z","timestamp":1622201600000},"page":"5773","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Chorioamnionitis Precipitates Perinatal Alterations of Heme-Oxygenase-1 (HO-1) Homeostasis in the Developing Rat Brain"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2020-7821","authenticated-orcid":false,"given":"Maide","family":"Ozen","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2232-4738","authenticated-orcid":false,"given":"Yuma","family":"Kitase","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Vasan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Burkhardt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sindhu","family":"Ramachandra","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenandoah","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Kennedy Krieger Institute, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren L.","family":"Jantzie","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Kennedy Krieger Institute, Baltimore, MD 21205, USA"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1159\/000362782","article-title":"Hypoxic\/ischemic and infectious events have cumulative effects on the risk of cerebral palsy in very-low-birth-weight preterm infants","volume":"106","author":"Wang","year":"2014","journal-title":"Neonatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1001\/jamapediatrics.2013.4248","article-title":"Chorioamnionitis and early childhood outcomes among extremely low-gestational-age neonates","volume":"168","author":"Pappas","year":"2014","journal-title":"JAMA Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1203\/PDR.0b013e3181bf5fab","article-title":"Microbiologic and histologic characteristics of the extremely preterm infant\u2019s placenta predict white matter damage and later cerebral palsy. the ELGAN study","volume":"67","author":"Leviton","year":"2010","journal-title":"Pediatr. 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