{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:22:14Z","timestamp":1785392534643,"version":"3.55.0"},"reference-count":38,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T00:00:00Z","timestamp":1628640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Following an intraventricular hemorrhage (IVH), red blood cell lysis and hemoglobin (Hb) oxidation with the release of heme can cause sterile neuroinflammation. In this study, we measured Hb derivates and cellular adhesion molecules ICAM-1 and VCAM-1 with cell-free miRNAs in cerebrospinal fluid (CSF) samples obtained from Grade-III and Grade-IV preterm IVH infants (IVH-III and IVH-IV, respectively) at multiple time points between days 0\u201360 after the onset of IVH. Furthermore, human choroid plexus epithelial cells (HCPEpiCs) were incubated with IVH and non-IVH CSF (10 v\/v %) for 24 h in vitro to investigate the IVH-induced inflammatory response that was investigated via: (i) HMOX1, IL8, VCAM1, and ICAM1 mRNAs as well as miR-155, miR-223, and miR-181b levels by RT-qPCR; (ii) nuclear translocation of the NF-\u03baB p65 subunit by fluorescence microscopy; and (iii) reactive oxygen species (ROS) measurement. We found a time-dependent alteration of heme, IL-8, and adhesion molecules which revealed a prolonged elevation in IVH-IV vs. IVH-III with higher miR-155 and miR-181b expression at days 41\u201360. Exposure of HCPEpiCs to IVH CSF samples induced HMOX1, IL8, and ICAM1 mRNA levels along with increased ROS production via the NF-\u03baB pathway activation but without cell death, as confirmed by the cell viability assay. Additionally, the enhanced intracellular miR-155 level was accompanied by lower miR-223 and miR-181b expression in HCPEpiCs after CSF treatment. Overall, choroid plexus epithelial cells exhibit an abnormal cell phenotype after interaction with pro-inflammatory CSF of IVH origin which may contribute to the development of later clinical complications in preterm IVH.<\/jats:p>","DOI":"10.3390\/ijms22168648","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T08:35:52Z","timestamp":1628670952000},"page":"8648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Preterm Intraventricular Hemorrhage-Induced Inflammatory Response in Human Choroid Plexus Epithelial Cells"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1387-2970","authenticated-orcid":false,"given":"Zsolt","family":"Fejes","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"P\u00f3csi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1652-4506","authenticated-orcid":false,"given":"Judit","family":"Erdei","sequence":"additional","affiliation":[{"name":"MTA-DE Lend\u00fclet Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"MTA-DE Lend\u00fclet Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enik\u0151","family":"Balogh","sequence":"additional","affiliation":[{"name":"MTA-DE Lend\u00fclet Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8837-7499","authenticated-orcid":false,"given":"\u00c1gnes","family":"Ruszny\u00e1k","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technologies, Faculty of Pharmacy, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"Doctoral School of Pharmaceutical Sciences, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2890-0783","authenticated-orcid":false,"given":"Ferenc","family":"Fenyvesi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technologies, Faculty of Pharmacy, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e1nos","family":"Kappelmayer","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4942-7091","authenticated-orcid":false,"given":"Vikt\u00f3ria","family":"Jeney","sequence":"additional","affiliation":[{"name":"MTA-DE Lend\u00fclet Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5700-3267","authenticated-orcid":false,"suffix":"Jr.","given":"B\u00e9la","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1167","DOI":"10.1542\/peds.2007-0423","article-title":"NICHD Research Network. Neurodevelopmental outcome of extremely low birth weight infants with posthemorrhagic hydrocephalus requiring shunt insertion","volume":"121","author":"Hansen","year":"2008","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1203\/PDR.0b013e3181c1b176","article-title":"Intraventricular hemorrhage in premature infants: Mechanism of disease","volume":"67","author":"Ballabh","year":"2010","journal-title":"Pediatr. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/S0022-3476(78)80282-0","article-title":"Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 gm","volume":"92","author":"Papile","year":"1978","journal-title":"J. Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1177\/0883073812463068","article-title":"ELGAN Study Investigators. Systemic inflammation, intraventricular hemorrhage, and white matter injury","volume":"28","author":"Leviton","year":"2013","journal-title":"J. Child Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3171\/jns.1998.89.4.0559","article-title":"Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage","volume":"89","author":"Polin","year":"1998","journal-title":"J. Neurosurg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"76","DOI":"10.4103\/1817-1745.57326","article-title":"Adhesion molecule levels in serum and cerebrospinal fluid in children with bacterial meningitis and sepsis","volume":"4","author":"Jaber","year":"2009","journal-title":"J. Pediatr. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"703571","DOI":"10.1155\/2013\/703571","article-title":"Natural history of the bruise: Formation, elimination, and biological effects of oxidized hemoglobin","volume":"2013","author":"Jeney","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12974-020-02052-4","article-title":"Cell-free oxidized hemoglobin drives reactive oxygen species production and pro-inflammation in an immature primary rat mixed glial cell culture","volume":"18","author":"Agyemang","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s12974-014-0200-9","article-title":"Extracellular hemoglobin\u2014Mediator of inflammation and cell death in the choroid plexus following preterm intraventricular hemorrhage","volume":"11","author":"Gram","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"228","DOI":"10.3389\/fimmu.2020.00228","article-title":"The Role of Hemoglobin Oxidation Products in Triggering Inflammatory Response Upon Intraventricular Hemorrhage in Premature Infants","volume":"11","author":"Erdei","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1182\/blood-2013-04-495887","article-title":"Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease","volume":"123","author":"Belcher","year":"2014","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1038\/nm.4361","article-title":"Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus","volume":"23","author":"Karimy","year":"2017","journal-title":"Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s12975-011-0070-8","article-title":"Inflammation of the choroid plexus and ependymal layer of the ventricle following intraventricular hemorrhage","volume":"2","author":"Simard","year":"2011","journal-title":"Transl. Stroke Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1146\/annurev-biochem-060308-103103","article-title":"Regulation of mRNA translation and stability by microRNAs","volume":"79","author":"Fabian","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/jmcb\/mjr007","article-title":"MicroRNAs in NF-kappaB signaling","volume":"3","author":"Ma","year":"2011","journal-title":"J. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1038\/ncomms4292","article-title":"HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells","volume":"5","author":"Tabet","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Pfeiffer, D., Ro\u00dfmanith, E., Lang, I., and Falkenhagen, D. (2017). miR-146a, miR-146b, and miR-155 increase expression of IL-6 and IL-8 and support HSP10 in an In vitro sepsis model. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179850"},{"key":"ref_18","first-page":"1973","article-title":"MicroRNA-181b regulates NF-\u03baB-mediated vascular inflammation","volume":"122","author":"Sun","year":"2012","journal-title":"J. Clin. Invest."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cao, D.D., Li, L., and Chan, W.Y. (2016). MicroRNAs: Key Regulators in the Central Nervous System and Their Implication in Neurological Diseases. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17060842"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/jcbfm.2010.101","article-title":"MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration","volume":"30","author":"Saugstad","year":"2010","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1161\/STROKEAHA.117.017804","article-title":"MicroRNA Changes in Cerebrospinal Fluid After Subarachnoid Hemorrhage","volume":"48","author":"Bache","year":"2017","journal-title":"Stroke"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"106141","DOI":"10.1016\/j.intimp.2019.106141","article-title":"MicroRNA-152 attenuates neuroinflammation in intracerebral hemorrhage by inhibiting thioredoxin interacting protein (TXNIP)-mediated NLRP3 inflammasome activation","volume":"80","author":"Hu","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Fejes, Z., Erdei, J., P\u00f3csi, M., Takai, J., Jeney, V., Nagy, A., Varga, A., B\u00e1csi, A., Bogn\u00e1r, L., and Nov\u00e1k, L. (2020). Elevated Pro-inflammatory Cell-Free MicroRNA Levels in Cerebrospinal Fluid of Premature Infants after Intraventricular Hemorrhage. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186870"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6622598","DOI":"10.1155\/2021\/6622598","article-title":"Germinal Matrix-Intraventricular Hemorrhage: A Tale of Preterm Infants","volume":"2021","author":"Egesa","year":"2021","journal-title":"Int. J. Pediatr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1007\/s00381-016-3217-9","article-title":"Role of selected cytokines in the etiopathogenesis of intraventricular hemorrhage in preterm newborns","volume":"32","author":"Szpecht","year":"2016","journal-title":"Childs Nerv. Syst."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S407","DOI":"10.1513\/AnnalsATS.201609-676AW","article-title":"A Hidden Epithelial Barrier in the Brain with a Central Role in Regulating Brain Homeostasis. Implications for Aging","volume":"13","author":"Vandenbroucke","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/s41374-020-0403-x","article-title":"Hemoglobin oxidation generates globin-derived peptides in atherosclerotic lesions and intraventricular hemorrhage of the brain, provoking endothelial dysfunction","volume":"100","author":"Posta","year":"2020","journal-title":"Lab. Invest."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3389\/fimmu.2020.00066","article-title":"Heme-Derived Metabolic Signals Dictate Immune Responses","volume":"11","author":"Canesin","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10435","DOI":"10.1038\/s41598-021-89713-3","article-title":"Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression","volume":"11","author":"Hendrik","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hong, J.Y., Kim, H., Jeon, W.J., Lee, J., and Ha, I.H. (2021). Elevated Mitochondrial Reactive Oxygen Species within Cerebrospinal Fluid as New Index in the Early Detection of Lumbar Spinal Stenosis. Diagnostics, 11.","DOI":"10.3390\/diagnostics11050748"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/1742-2094-10-100","article-title":"Hemoglobin induces inflammation after preterm intraventricular hemorrhage by methemoglobin formation","volume":"10","author":"Gram","year":"2013","journal-title":"J. Neuroinflamm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1093\/jnen\/nlv030","article-title":"The Choroid Plexus in Healthy and Diseased Brain","volume":"75","author":"Kaur","year":"2016","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1186\/s12974-015-0424-3","article-title":"MicroRNA367 negatively regulates the inflammatory response of microglia by targeting IRAK4 in intracerebral hemorrhage","volume":"12","author":"Yuan","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Zhang, W., Wang, L., Wang, R., Duan, Z., and Wang, H. (2020). A blockade of microRNA-155 signal pathway has a beneficial effect on neural injury after intracerebral haemorrhage via reduction in neuroinflammation and oxidative stress. Arch. Physiol. Biochem.","DOI":"10.1080\/13813455.2020.1764047"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ab.2017.01.002","article-title":"Determination of extinction coefficients of human hemoglobin in various redox states","volume":"521","author":"Meng","year":"2017","journal-title":"Anal. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1160\/TH16-04-0322","article-title":"Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus","volume":"117","author":"Fejes","year":"2017","journal-title":"Thromb. Haemost."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Czimmerer, Z., Hulvely, J., Simandi, Z., Varallyay, E., Havelda, Z., Szabo, E., Varga, A., Dezso, B., Balogh, M., and Horvath, A. (2013). A versatile method to design stem-loop primer-based quantitative PCR assays for detecting small regulatory RNA molecules. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055168"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Fejes, Z., Czimmerer, Z., Sz\u00fck, T., P\u00f3liska, S., Horv\u00e1th, A., Balogh, E., Jeney, V., V\u00e1radi, J., Fenyvesi, F., and Balla, G. (2018). Endothelial cell activation is attenuated by everolimus via transcriptional and post-transcriptional regulatory mechanisms after drug-eluting coronary stenting. 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