Correction: The Human Endogenous Protection System against Cell-Free Hemoglobin and Heme Is Overwhelmed in Preeclampsia and Provides Potential Biomarkers and Clinical Indicators.

[This corrects the article DOI: 10.1371/journal.pone.0138111.].

Altered Tryptophan Catabolism in Placentas From Women With Pre-eclampsia.

BACKGROUND: The kynurenine pathway enzymes, breaking down tryptophan, are abundant in placental tissue. These metabolites are involved in immunoregulatory mechanisms, although the role of this pathway in pre-eclampsia (PE) has only begun to be characterized. Here, we determined tryptophan and metabolite levels together with the expression of kynurenine pathway enzymes and inflammatory factors in placental tissue from women with and without PE. METHODS: Thirty-six placentas (18 PE and 18 controls) were analyzed for expression of kynurenine pathway enzymes indoleamine-2,3-dioxygenase (IDO1 and 2), tryptophan-2,3-dioxygenase (TDO), kynurenine-3-mono-oxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) as well as interleukin (IL)-1ß, IL-6, and serum amyloid A (SAA). Tryptophan and kynurenine content were measured using high-pressure liquid chromatography and quinolinic acid was measured using gas chromatography-mass spectrometry. CONCLUSIONS: Tryptophan content was reduced in placentas from women with PE. There was an increased kynurenine/tryptophan ratio in placentas from women with PE but no significant change in downstream metabolites. We confirmed a reduction in IDO1 expression and found a compensatory increase in TDO expression in placentas from women with PE. SAA was reduced in PE placentas compared with controls. Our data show that tryptophan content and the inflammatory mediator SAA are both compromised in placentas from women with PE. Further studies on the role of tryptophan catabolism and mediators of inflammation in sustaining healthy immunobiological pathways in the placenta are warranted.

The hemoglobin degradation pathway in patients with preeclampsia - Fetal hemoglobin, heme, heme oxygenase-1 and hemopexin - Potential diagnostic biomarkers?

OBJECTIVE: The aim of this study was to investigate how maternal cell-free fetal hemoglobin and heme impact the scavenger enzyme systems Hemopexin and Heme Oxygenase-1 in patients with preeclampsia (PE). The secondary aims were to evaluate these proteins as biomarkers for severity of the clinical manifestation i.e. hypertension, in early- and late onset PE. MATERIAL AND METHODS: Plasma samples taken within the last 24 h before delivery from 135 patients were analyzed, 89 PE and 46 normal pregnancies. All samples were analyzed for cell-free fetal hemoglobin (HbF), heme, hemopexin enzymatic activity (Hx activity), hemopexin concentration (Hx), and heme oxygenase 1 concentration (HO-1). Logistic regression analysis with ROC-curve analysis was performed to evaluate the possible use as biomarkers for preeclampsia. RESULTS: There were significantly higher levels of HbF (p = 0.01) and heme (0.01) but significantly lower Hx activity (p = 0.02), Hx (p < 0.0001) and HO-1 (p = 0.03) in PE plasma as compared to plasma of normal pregnancies. The Hx activity was significantly inversely correlated (p = 0.04) to the diastolic blood pressure. The HO-1 concentration was significantly inversely correlated to both the systolic and diastolic blood pressure (p = 0.01 and p = 0.003). ROC-curve analysis showed a combined detection rate for these biomarkers of 84% at 10% false positive rate. CONCLUSIONS: Increased maternal plasma levels of heme and HbF in PE are associated with decreased HO-1 and hemopexin protein levels as well as reduced hemopexin activity. By measuring the consumption of the scavenger protein Hx, and the proteins in the Hb degradation system, clinical information about the dynamics of the disease can be obtained.

Fetal sex-specific differences in gestational age at delivery in pre-eclampsia: a meta-analysis.

Background: : Pre-eclampsia (PE) is a major pregnancy disorder complicating up to 8% of pregnancies. Increasing evidence indicates a sex-specific interplay between the mother, placenta and fetus. This may lead to different adaptive mechanisms during pregnancy. Methods: We performed an individual participant data meta-analysis to determine associations of fetal sex and PE, with specific focus on gestational age at delivery in PE. This was done on 219 575 independent live-born singleton pregnancies, with a gestational age at birth between 22.0 and 43.0 weeks of gestation, from 11 studies participating in a worldwide consortium of international research groups focusing on pregnancy. Results: Of the women, 9033 (4.1%) experienced PE in their pregnancy and 48.8% of the fetuses were female versus 51.2% male. No differences in the female/male distribution were observed with respect to term PE (delivered ≥ 37 weeks). Preterm PE (delivered < 37 weeks) was slightly more prevalent among pregnancies with a female fetus than in pregnancies with a male fetus [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.02-1.21]. Very preterm PE (delivered < 34 weeks) was even more prevalent among pregnancies with a female fetus as compared with pregnancies with a male fetus (OR 1.36, 95% CI 1.17-1.59). Conclusions: Sexual dimorphic differences in the occurrence of PE exist, with preterm PE being more prevalent among pregnancies with a female fetus as compared with pregnancies with a male fetus and with no differences with respect to term PE.

The Human Endogenous Protection System against Cell-Free Hemoglobin and Heme Is Overwhelmed in Preeclampsia and Provides Potential Biomarkers and Clinical Indicators.

Preeclampsia (PE) complicates 3-8% of all pregnancies and manifests clinically as hypertension and proteinuria in the second half of gestation. The pathogenesis of PE is not fully understood but recent studies have described the involvement of cell-free fetal hemoglobin (HbF). Hypothesizing that PE is associated with prolonged hemolysis we have studied the response of the cell-free Hb- and heme defense network. Thus, we have investigated the levels of cell-free HbF (both free, denoted HbF, and in complex with Hp, denoted Hp-HbF) as well as the major human endogenous Hb- and heme-scavenging systems: haptoglobin (Hp), hemopexin (Hpx), α1-microglobulin (A1M) and CD163 in plasma of PE women (n = 98) and women with normal pregnancies (n = 47) at term. A significant increase of the mean plasma HbF concentration was observed in women with PE. Plasma levels of Hp and Hpx were statistically significantly reduced, whereas the level of the extravascular heme- and radical scavenger A1M was significantly increased in plasma of women with PE. The Hpx levels significantly correlated with maternal blood pressure. Furthermore, HbF and the related scavenger proteins displayed a potential to be used as clinical biomarkers for more precise diagnosis of PE and are candidates as predictors of identifying pregnancies with increased risk of obstetrical complications. The results support that PE pathophysiology is associated with increased HbF-concentrations and an activation of the physiological Hb-heme defense systems.