title: A1M Ameliorates Preeclampsia-Like Symptoms in Placenta and Kidney Induced by Cell-Free Fetal Hemoglobin in Rabbit.
abstract: Preeclampsia is one of the most serious pregnancy-related diseases and clinically manifests as hypertension and proteinuria after 20 gestational weeks. The worldwide prevalence is 3-8% of pregnancies, making it the most common cause of maternal and fetal morbidity and mortality. Preeclampsia lacks an effective therapy, and the only "cure" is delivery. We have previously shown that increased synthesis and accumulation of cell-free fetal hemoglobin (HbF) in the placenta is important in the pathophysiology of preeclampsia. Extracellular hemoglobin (Hb) and its metabolites induce oxidative stress, which may lead to acute renal failure and vascular dysfunction seen in preeclampsia. The human endogenous protein, α1-microglobulin (A1M), removes cell-free heme-groups and induces natural tissue repair mechanisms. Exogenously administered A1M has been shown to alleviate the effects of Hb-induced oxidative stress in rat kidneys. Here we attempted to establish an animal model mimicking the human symptoms at stage two of preeclampsia by administering species-specific cell-free HbF starting mid-gestation until term, and evaluated the therapeutic effect of A1M on the induced symptoms. Female pregnant rabbits received HbF infusions i.v. with or without A1M every second day from gestational day 20. The HbF-infused animals developed proteinuria and a significantly increased glomerular sieving coefficient in kidney that was ameliorated by co-administration of A1M. Transmission electron microscopy analysis of kidney and placenta showed both intracellular and extracellular tissue damages after HbF-treatment, while A1M co-administration resulted in a significant reduction of the structural and cellular changes. Neither of the HbF-treated animals displayed any changes in blood pressure during pregnancy. In conclusion, infusion of cell-free HbF in the pregnant rabbits induced tissue damage and organ failure similar to those seen in preeclampsia, and was restored by co-administration of A1M. This study provides preclinical evidence supporting further examination of A1M as a potential new therapy for preeclampsia.
authors.affiliation: Obstetrics and Gynecology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Nääv
authors.affiliation: Obstetrics and Gynecology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Erlandsson
authors.affiliation: Nephrology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Josefin
authors.initials: J
authors.lastname: Axelsson
authors.affiliation: Obstetrics and Gynecology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Irene
authors.initials: I
authors.lastname: Larsson
authors.affiliation: Clinical Pathology, Department of Laboratory Medicine, Lund University, Malmö, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Infection Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Wester-Rosenlöf
authors.affiliation: Infection Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: Obstetrics and Gynecology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Vera
authors.initials: V
authors.lastname: Casslén
authors.affiliation: Infection Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Gram
authors.affiliation: Infection Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Åkerström
authors.affiliation: Obstetrics and Gynecology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Hansson
mesh_terms: D000510:Alpha-Globulins / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D005319:Fetal Hemoglobin / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000378:metabolism; D006418:Heme / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011225:Pre-Eclampsia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011247:Pregnancy; D011507:Proteinuria / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011817:Rabbits
chemical_list: D000510:Alpha-Globulins; C016001:alpha-1-microglobulin; D006418:Heme; D005319:Fetal Hemoglobin