A1M/α1-microglobulin protects from heme-induced placental and renal damage in a pregnant sheep model of preeclampsia.
Preeclampsia (PE) is a serious pregnancy complication that manifests as hypertension and proteinuria after the 20(th) gestation week. Previously, fetal hemoglobin (HbF) has been identified as a plausible causative factor. Cell-free Hb and its degradation products are known to cause oxidative stress and tissue damage, typical of the PE placenta. A1M (α1-microglobulin) is an endogenous scavenger of radicals and heme. Here, the usefulness of A1M as a treatment for PE is investigated in the pregnant ewe PE model, in which starvation induces PE symptoms via hemolysis. Eleven ewes, in late pregnancy, were starved for 36 hours and then treated with A1M (n = 5) or placebo (n = 6) injections. After injections, the ewes were re-fed and observed for additional 72 hours. They were monitored for blood pressure, proteinuria, blood cell distribution and clinical and inflammation markers in plasma. Before termination, the utero-placental circulation was analyzed with Doppler velocimetry and the kidney glomerular function was analyzed by Ficoll sieving. At termination, blood, kidney and placenta samples were collected and analyzed for changes in gene expression and tissue structure. The starvation resulted in increased amounts of the hemolysis marker bilirubin in the blood, structural damages to the placenta and kidneys and an increased glomerular sieving coefficient indicating a defect filtration barrier. Treatment with A1M ameliorated these changes without signs of side-effects. In conclusion, A1M displayed positive therapeutic effects in the ewe starvation PE model, and was well tolerated. Therefore, we suggest A1M as a plausible treatment for PE in humans.
Department of Infection Medicine, Lund University, Lund, Sweden.
Lena
L
Wester-Rosenlöf
Department of Obstetrics and Gynecology, Lund University, Lund, Sweden.
Vera
V
Casslén
Department of Nephrology, Lund University, Lund, Sweden.
Josefin
J
Axelsson
Department of Infection Medicine, Lund University, Lund, Sweden.
Anneli
A
Edström-Hägerwall
Department of Infection Medicine, Lund University, Lund, Sweden.
Magnus
M
Gram
Department of Obstetrics and Gynecology, Lund University, Lund, Sweden.
Madlene
M
Holmqvist
Department of Laboratory Medicine, Lund University, Malmö, Sweden.
Martin E
ME
Johansson
Department of Obstetrics and Gynecology, Lund University, Lund, Sweden.
Iréne
I
Larsson
Department of Pediatrics, Lund University, Lund, Sweden.
David
D
Ley
Department of Obstetrics and Gynecology, Lund University, Lund, Sweden.
Karel
K
Marsal
Department of Infection Medicine, Lund University, Lund, Sweden.
Matthias
M
Mörgelin
Department of Nephrology, Lund University, Lund, Sweden.
Bengt
B
Rippe
Department of Infection Medicine, Lund University, Lund, Sweden.
Sigurbjörg
S
Rutardottir
Department of Obstetrics and Gynecology, Lund University, Lund, Sweden.
Behnaz
B
Shohani
Department of Infection Medicine, Lund University, Lund, Sweden.
Bo
B
Akerström
Department of Obstetrics and Gynecology, Lund University, Lund, Sweden.
Stefan R
SR
Hansson
D000510:Alpha-Globulins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D006418:Heme / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000378:metabolism*; D011247:Pregnancy
D000510:Alpha-Globulins; C016001:alpha-1-microglobulin; D006418:Heme