{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:10:04Z","timestamp":1792523404863,"version":"4.5.0"},"reference-count":110,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T00:00:00Z","timestamp":1595980800000},"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>Both infectious as non-infectious inflammation can cause placental dysfunction and pregnancy complications. During the first trimester of human gestation, when palatogenesis takes place, intrauterine hematoma and hemorrhage are common phenomena, causing the release of large amounts of heme, a well-known alarmin. We postulated that exposure of pregnant mice to heme during palatogenesis would initiate oxidative and inflammatory stress, leading to pathological pregnancy, increasing the incidence of palatal clefting and abortion. Both heme oxygenase isoforms (HO-1 and HO-2) break down heme, thereby generating anti-oxidative and -inflammatory products. HO may thus counteract these heme-induced injurious stresses. To test this hypothesis, we administered heme to pregnant CD1 outbred mice at Day E12 by intraperitoneal injection in increasing doses: 30, 75 or 150 \u03bcmol\/kg body weight (30H, 75H or 150H) in the presence or absence of HO-activity inhibitor SnMP from Day E11. Exposure to heme resulted in a dose-dependent increase in abortion. At 75H half of the fetuses where resorbed, while at 150H all fetuses were aborted. HO-activity protected against heme-induced abortion since inhibition of HO-activity aggravated heme-induced detrimental effects. The fetuses surviving heme administration demonstrated normal palatal fusion. Immunostainings at Day E16 demonstrated higher numbers of ICAM-1 positive blood vessels, macrophages and HO-1 positive cells in placenta after administration of 75H or SnMP + 30H. Summarizing, heme acts as an endogenous \u201calarmin\u201d during pregnancy in a dose-dependent fashion, while HO-activity protects against heme-induced placental vascular inflammation and abortion.<\/jats:p>","DOI":"10.3390\/ijms21155385","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T07:31:45Z","timestamp":1596007905000},"page":"5385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Heme Oxygenase Protects against Placental Vascular Inflammation and Abortion by the Alarmin Heme in Mice"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0568-438X","authenticated-orcid":false,"given":"Christiaan M.","family":"Suttorp","sequence":"first","affiliation":[{"name":"Department of Dentistry\u2014Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6525 EX Nijmegen, The Netherlands"},{"name":"Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 E. M.","family":"van Rheden","sequence":"additional","affiliation":[{"name":"Department of Dentistry\u2014Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6525 EX Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasja W. M.","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Dentistry\u2014Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6525 EX Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria P. A. C.","family":"Helmich","sequence":"additional","affiliation":[{"name":"Department of Dentistry\u2014Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6525 EX Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Marie","family":"Kuijpers-Jagtman","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"},{"name":"Department of Orthodontics and Dentofacial Orthopedics, University of Bern, CH-3010 Bern, Switzerland"},{"name":"Faculty of Dentistry, Universitas Indonesia, Jakarta ID-10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4837-1559","authenticated-orcid":false,"given":"Frank A. D. T. G.","family":"Wagener","sequence":"additional","affiliation":[{"name":"Department of Dentistry\u2014Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6525 EX Nijmegen, The Netherlands"},{"name":"Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000337464","article-title":"Epidemiology of oral clefts 2012: An international perspective","volume":"16","author":"Mossey","year":"2012","journal-title":"Front. Oral Biol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Krishnan, V., and Davidovitch, Z. (2012). Cleft Lip and Palate: Role of the Orthodontist in the Inderdisciplinary Management Team. 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