title: Hypoxic treatment of human dual placental perfusion induces a preeclampsia-like inflammatory response.
abstract: Preeclampsia is a human pregnancy-specific disorder characterized by a placental pro-inflammatory response in combination with an imbalance of angiogenic factors and clinical symptoms, including hypertension and proteinuria. Insufficient uteroplacental oxygenation in preeclampsia due to impaired trophoblast invasion during placentation is believed to be responsible for many of the molecular events leading to the clinical manifestations of this disease. We investigated the use of hypoxic treatment of the dual placental perfusion system as a model for preeclampsia. A modified perfusion technique allowed us to achieve a mean soluble oxygen tension within the intervillous space (IVS) of 5-7% for normoxia and <3% for hypoxia (as a model for preeclampsia). We assayed for the levels of different inflammatory cytokines, oxidative stress markers, as well as other factors, such as endothelin (ET)-1 that are known to be implicated as part of the inflammatory response in preeclampsia. Our results show a significant increase under hypoxia in the levels of different inflammatory cytokines, including IL-6 (P=0.002), IL-8 (P<0.0001), TNF-α (P=0.032) and IFN-γ (P=0.009) at 360 min in maternal venous samples (n=6). There was also a significant increase in ET-1 levels under hypoxia both on the maternal side at 30 min (P=0.003) and fetal side at 360 min (P=0.036) (n=6). Other markers of oxidative stress, including malondialdehyde and 8-iso-protaglandin F2α (P=0.009) also show increased levels. Overall, these findings indicate that exposure of ex vivo dually perfused placental tissue to hypoxia provides a useful model for mimicking the inflammatory response characteristic of preeclampsia. This would therefore provide a powerful tool for studying and further delineating the molecular mechanisms involved in the underlying pathophysiology of preeclampsia.
authors.affiliation: 1] Faculty of Medicine, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland [2] Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland [3] Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Arjun
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Henning
authors.initials: H
authors.lastname: Schneider
authors.affiliation: Faculty of Medicine, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
authors.forename: Eldar
authors.initials: E
authors.lastname: Aliyev
authors.affiliation: 1] Maternal and Fetal Health Research Centre, Faculty of Human and Medical Science, The University of Manchester, Manchester, UK [2] St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Fatimah
authors.initials: F
authors.lastname: Soydemir
authors.affiliation: 1] Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland [2] Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Baumann
authors.affiliation: 1] Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland [2] Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Surbek
authors.affiliation: 1] Faculty of Medicine, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland [2] Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hediger
authors.affiliation: 1] Maternal and Fetal Health Research Centre, Faculty of Human and Medical Science, The University of Manchester, Manchester, UK [2] St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Brownbill
authors.affiliation: 1] Faculty of Medicine, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland [2] Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
authors.forename: Christiane
authors.initials: C
authors.lastname: Albrecht
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015687:Cell Hypoxia; D016207:Cytokines / Q000378:metabolism*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D015227:Lipid Peroxidation; D008315:Malondialdehyde / Q000378:metabolism; D018384:Oxidative Stress; D010477:Perfusion; D010920:Placenta / Q000098:blood supply / Q000276:immunology / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000276:immunology / Q000378:metabolism*; D011247:Pregnancy; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D016207:Cytokines; D019332:Endothelin-1; C075750:8-epi-prostaglandin F2alpha; D008315:Malondialdehyde; D015237:Dinoprost