Publications by authors named "Irina Burd"

120 Publications

Fetal Neuroprotective Strategies: Therapeutic Agents and Their Underlying Synaptic Pathways.

Front Synaptic Neurosci 2021 23;13:680899. Epub 2021 Jun 23.

Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Synaptic signaling is integral for proper brain function. During fetal development, exposure to inflammation or mild hypoxic-ischemic insult may lead to synaptic changes and neurological damage that impairs future brain function. Preterm neonates are most susceptible to these deleterious outcomes. Evaluating clinically used and novel fetal neuroprotective measures is essential for expanding treatment options to mitigate the short and long-term consequences of fetal brain injury. Magnesium sulfate is a clinical fetal neuroprotective agent utilized in cases of imminent preterm birth. By blocking N-methyl-D-aspartate receptors, magnesium sulfate reduces glutamatergic signaling, which alters calcium influx, leading to a decrease in excitotoxicity. Emerging evidence suggests that melatonin and N-acetyl-L-cysteine (NAC) may also serve as novel putative fetal neuroprotective candidates. Melatonin has important anti-inflammatory and antioxidant properties and is a known mediator of synaptic plasticity and neuronal generation. While NAC acts as an antioxidant and a precursor to glutathione, it also modulates the glutamate system. Glutamate excitotoxicity and dysregulation can induce perinatal preterm brain injury through damage to maturing oligodendrocytes and neurons. The improved drug efficacy and delivery of the dendrimer-bound NAC conjugate provides an opportunity for enhanced pharmacological intervention. Here, we review recent literature on the synaptic pathways underlying these therapeutic strategies, discuss the current gaps in knowledge, and propose future directions for the field of fetal neuroprotective agents.
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http://dx.doi.org/10.3389/fnsyn.2021.680899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262796PMC
June 2021

Dexamethasone for Severe COVID-19: How Does It Work at Cellular and Molecular Levels?

Int J Mol Sci 2021 Jun 23;22(13). Epub 2021 Jun 23.

Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

The coronavirus disease 2019 (COVID-19) caused by infection of the severe respiratory syndrome coronavirus-2 (SARS-CoV-2) significantly impacted human society. Recently, the synthetic pure glucocorticoid dexamethasone was identified as an effective compound for treatment of severe COVID-19. However, glucocorticoids are generally harmful for infectious diseases, such as bacterial sepsis and severe influenza pneumonia, which can develop respiratory failure and systemic inflammation similar to COVID-19. This apparent inconsistency suggests the presence of pathologic mechanism(s) unique to COVID-19 that renders this steroid effective. We review plausible mechanisms and advance the hypothesis that SARS-CoV-2 infection is accompanied by infected cell-specific glucocorticoid insensitivity as reported for some other viruses. This alteration in local glucocorticoid actions interferes with undesired glucocorticoid to facilitate viral replication but does not affect desired anti-inflammatory properties in non-infected organs/tissues. We postulate that the virus coincidentally causes glucocorticoid insensitivity in the process of modulating host cell activities for promoting its replication in infected cells. We explore this tenet focusing on SARS-CoV-2-encoding proteins and potential molecular mechanisms supporting this hypothetical glucocorticoid insensitivity unique to COVID-19 but not characteristic of other life-threatening viral diseases, probably due to a difference in specific virally-encoded molecules and host cell activities modulated by them.
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http://dx.doi.org/10.3390/ijms22136764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269070PMC
June 2021

The Israeli study of Pfizer BNT162b2 vaccine in pregnancy: considering maternal and neonatal benefits.

J Clin Invest 2021 07;131(13)

Division of Reproductive Sciences, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Pregnant patients with COVID-19 are more likely to require intensive care and die compared with noninfected pregnant women. While the consequences of COVID-19 disease in pregnancy prompted many health care organizations to support vaccination in pregnancy, vaccine effects for mother and infant remained unclear. In this issue of the JCI, Beharier and Mayo et al. explored maternal and neonatal responses to the Pfizer BNT162b2 SARS-CoV-2 mRNA vaccine. The authors examined blood samples from women and cord blood of neonates following childbirth. Samples were stratified into three groups: vaccine recipients, unvaccinated participants with past positive SARS-CoV-2 test, and unvaccinated participants without prior infection. Vaccinated mothers and mothers with previous infection generated and transferred protective IgG antibodies across the placenta. This study provides evidence to support the safety and efficacy of COVID-19 vaccination in pregnancy with protection to the neonate against infection, outlining clear vaccine benefits for both maternal and child health.
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http://dx.doi.org/10.1172/JCI150790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245166PMC
July 2021

Pregnancy alters interleukin-1 beta expression and antiviral antibody responses during severe acute respiratory syndrome coronavirus 2 infection.

Am J Obstet Gynecol 2021 Mar 30. Epub 2021 Mar 30.

Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Background: Severe acute respiratory syndrome coronavirus 2, the disease-causing pathogen of the coronavirus disease 2019 pandemic, has resulted in morbidity and mortality worldwide. Pregnant women are more susceptible to severe coronavirus disease 2019 and are at higher risk of preterm birth than uninfected pregnant women. Despite this evidence, the immunologic effects of severe acute respiratory syndrome coronavirus 2 infection during pregnancy remain understudied.

Objective: This study aimed to assess the impact of severe acute respiratory syndrome coronavirus 2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to severe acute respiratory syndrome coronavirus 2 among pregnant and nonpregnant women.

Study Design: Immune responses to severe acute respiratory syndrome coronavirus 2 were analyzed using samples from pregnant (n=33) and nonpregnant (n=17) women who tested either positive (pregnant, 22; nonpregnant, 17) or negative for severe acute respiratory syndrome coronavirus 2 (pregnant, 11) at Johns Hopkins Hospital. We measured proinflammatory and placental cytokine messenger RNAs, neonatal Fc receptor expression, and tetanus antibody transfer in maternal and cord blood samples. In addition, we evaluated antispike immunoglobulin G, antispike receptor-binding domain immunoglobulin G, and neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in serum or plasma collected from nonpregnant women, pregnant women, and cord blood.

Results: Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection expressed more interleukin-1 beta, but not interleukin 6, in blood samples collected within 14 days vs >14 days after performing severe acute respiratory syndrome coronavirus 2 test. Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection also had reduced antispike receptor-binding domain immunoglobulin G titers and were less likely to have detectable neutralizing antibody than nonpregnant women. Although severe acute respiratory syndrome coronavirus 2 infection did not disrupt neonatal Fc receptor expression in the placenta, maternal transfer of severe acute respiratory syndrome coronavirus 2 neutralizing antibody was inhibited by infection during pregnancy.

Conclusion: Severe acute respiratory syndrome coronavirus 2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of coronavirus disease 2019 treatment in pregnancy. In addition, the long-term implications of placental inflammation for neonatal health require greater consideration.
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http://dx.doi.org/10.1016/j.ajog.2021.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008823PMC
March 2021

COVID-19 vaccine testing in pregnant females is necessary.

J Clin Invest 2021 03;131(5)

Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1172/JCI147553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919709PMC
March 2021

Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth.

Sci Transl Med 2021 01;13(576)

Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Inflammation contributes to nearly 4 million global premature births annually. Here, we used a mouse model of intrauterine inflammation to test clinically used formulations, as well as engineered nanoformulations, for the prevention of preterm birth (PTB). We observed that neither systemic 17a-hydroxyprogesterone caproate (Makena) nor vaginal progesterone gel (Crinone) was sufficient to prevent inflammation-induced PTB, consistent with recent clinical trial failures. However, we found that vaginal delivery of mucoinert nanosuspensions of histone deacetylase (HDAC) inhibitors, in some cases with the addition of progesterone, prevented PTB and resulted in delivery of live pups exhibiting neurotypical development. In human myometrial cells in vitro, the P4/HDAC inhibitor combination both inhibited cell contractility and promoted the anti-inflammatory action of P4 by increasing progesterone receptor B stability. Here, we demonstrate the use of vaginally delivered drugs to prevent intrauterine inflammation-induced PTB resulting in the birth of live offspring in a preclinical animal model.
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http://dx.doi.org/10.1126/scitranslmed.abc6245DOI Listing
January 2021

Maternal Hypertensive Disorders in Pregnancy and Postpartum Plasma B Vitamin and Homocysteine Profiles in a High-Risk Multiethnic U.S., Population.

J Womens Health (Larchmt) 2020 12 16;29(12):1520-1529. Epub 2020 Nov 16.

Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.

Hypertensive disorders of pregnancy are a recognized risk factor of a woman's future cardiovascular risk. The potential role of micronutrients in mitigating hypertensive disorders is not fully understood. This study examined maternal postpartum plasma B vitamin profiles by hypertensive disorders of pregnancy in a high-risk multiethnic U.S. population. The analyses included 2584 mothers enrolled within 3 days postpartum at the Boston Medical Center. Hypertensive disorders of pregnancy included gestational hypertension and pre-eclampsia disorders (pre-eclampsia, eclampsia, hemolysis, elevated liver enzymes, and/or low platelets syndrome) as documented in the medical records. Plasma folate, vitamin B12, and homocysteine levels were measured in blood samples collected at enrollment. Kernel density plots and multivariable regressions were used to examine the relationship between hypertensive disorders and postpartum B vitamin profiles. Of the 2584 mothers, 10% had pre-eclampsia disorders that were associated with significantly lower plasma folate (adjusted beta coefficient (aβ): -0.10; 95% CI: -0.22 to -0.06) and increased homocysteine (aβ: 0.08; 95% CI: 0.04-0.13), but not with vitamin B12 concentrations. These associations remained robust after adjusting for a range of pertinent covariables and were more pronounced in non-Hispanic Black women compared with other groups. However, gestational hypertension was not significantly associated with any postpartum biomarker. We found that pre-eclampsia disorders, but not gestational hypertension, was associated with lower folate and higher homocysteine levels postpartum, especially among Black mothers. This finding, if further confirmed, may have implications for postpartum care, including attention to maternal micronutrient status to reduce and prevent hypertensive disorders in pregnancy-associated consequences in subsequent pregnancies and lifespan. Registration date: July 25, 2017; Registry website: https://clinicaltrials.gov/ct2/show/NCT03228875.
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http://dx.doi.org/10.1089/jwh.2020.8420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757544PMC
December 2020

Dysregulated immunity in SARS-CoV-2 infected pregnant women.

medRxiv 2020 Nov 16. Epub 2020 Nov 16.

Importance: The effects of SARS-CoV-2 infection on immune responses during pregnancy have not been systematically evaluated.

Objective: To assess the impact of SARS-CoV-2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to SARS-CoV-2 among pregnant and non-pregnant women.

Design: Immune responses to SARS-CoV-2 were analyzed using samples from pregnant and non-pregnant women who had either tested positive or negative for SARS-CoV-2. We measured, proinflammatory and placental cytokine mRNAs, neonatal Fc receptor (FcRn) receptor expression, and tetanus antibody transfer in maternal and cord blood samples. Additionally, we measured anti-spike (S) IgG, anti-S-receptor binding domain (RBD) IgG, and neutralizing antibody (nAb) responses to SARS-CoV-2 in serum or plasma collected from non-pregnant women, pregnant women, and cord blood.

Setting: Johns Hopkins Hospital (JHH).

Participants: Pregnant women were recruited through JHH outpatient obstetric clinics and the JHH Labor & Delivery unit. Non-pregnant women were recruited after receiving outpatient SARS-CoV-2 testing within Johns Hopkins Health System, USA. Adult non-pregnant women with positive RT-PCR results for SARS-CoV-2, within the age range of 18-48 years, were included in the study.

Exposures: SARS-CoV-2.

Main Outcomes And Measures: Participant demographic characteristics, antibody titers, cytokine mRNA expression, and FcRn receptor expression.

Results: SARS-COV-2 positive pregnant women expressed more , but not , in blood samples collected within 14 days versus > 14 days after a confirmed SARS-CoV-2 test, with similar patterns observed in the fetal side of placentas, particularly among asymptomatic pregnant women. Pregnant women with confirmed SARS-CoV-2 infection also had reduced anti-S-RBD IgG titers and were less likely to have detectable nAb as compared with non-pregnant women. Although SARS-CoV-2 infection did not disrupt FcRn expression in the placenta, maternal transfer of nAb was inhibited by SARS-CoV-2 infection during pregnancy.

Conclusions And Relevance: SARS-CoV-2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of COVID-19 therapeutics in pregnancy. The long-term implications of placental inflammation for neonatal health also requires greater consideration.
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http://dx.doi.org/10.1101/2020.11.13.20231373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685337PMC
November 2020

Antenatal Monitoring After Preterm Prelabor Rupture of Membranes.

Obstet Gynecol Clin North Am 2020 Dec;47(4):625-632

Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Phipps 228, Baltimore, MD 21287-4922, USA. Electronic address:

Preterm prelabor rupture of membranes is a complication of pregnancy with significant associated maternal and fetal risks. Expectant management of this complication requires inpatient admission with close monitoring of maternal and fetal status until delivery. Close antepartum monitoring ensures rapid intervention if indicated, allowing for best possible maternal and neonatal outcomes.
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http://dx.doi.org/10.1016/j.ogc.2020.08.009DOI Listing
December 2020

Role of Inflammation in Virus Pathogenesis during Pregnancy.

J Virol 2020 12 22;95(2). Epub 2020 Dec 22.

Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Viral infections during pregnancy lead to a spectrum of maternal and fetal outcomes, ranging from asymptomatic disease to more critical conditions presenting with severe maternal morbidity, stillbirth, preterm birth, intrauterine growth restriction, and fetal congenital anomalies, either apparent at birth or later in life. In this article, we review the pathogenesis of several viral infections that are particularly relevant in the context of pregnancy and intrauterine inflammation. Understanding the diverse mechanisms employed by viral pathogens as well as the repertoire of immune responses induced in the mother may help to establish novel therapeutic options to attenuate changes in the maternal-fetal interface and prevent adverse pregnancy outcomes.
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http://dx.doi.org/10.1128/JVI.01381-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944452PMC
December 2020

Animal models of congenital zika syndrome provide mechanistic insight into viral pathogenesis during pregnancy.

PLoS Negl Trop Dis 2020 10 22;14(10):e0008707. Epub 2020 Oct 22.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.

In utero Zika virus (ZIKV; family Flaviviridae) infection causes a distinct pattern of birth defects and disabilities in the developing fetus and neonate that has been termed congenital zika syndrome (CZS). Over 8,000 children were affected by the 2016 to 2017 ZIKV outbreak in the Americas, many of whom developed CZS as a result of in utero exposure. To date, there is no consensus about how ZIKV causes CZS; animal models, however, are providing mechanistic insights. Using nonhuman primates, immunocompromised mice, immunocompetent mice, and other animal models (e.g., pigs, sheep, guinea pigs, and hamsters), studies are showing that maternal immunological responses, placental infection and inflammation, as well as viral genetic factors play significant roles in predicting the downstream consequences of in utero ZIKV infection on the development of CZS in offspring. There are thousands of children suffering from adverse consequences of CZS. Therefore, the animal models developed to study ZIKV-induced adverse outcomes in offspring could provide mechanistic insights into how other viruses, including influenza and hepatitis C viruses, impact placental viability and fetal growth to cause long-term adverse outcomes in an effort to identify therapeutic treatments.
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http://dx.doi.org/10.1371/journal.pntd.0008707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580937PMC
October 2020

Postpartum plasma metabolomic profile among women with preeclampsia and preterm delivery: implications for long-term health.

BMC Med 2020 10 13;18(1):277. Epub 2020 Oct 13.

Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe St, Baltimore, MD, 21205-2179, USA.

Background: Preeclampsia and preterm delivery (PTD) are believed to affect women's long-term health including cardiovascular disease (CVD), but the biological underpinnings are largely unknown. We aimed to test whether maternal postpartum metabolomic profiles, especially CVD-related metabolites, varied according to PTD subtypes with and without preeclampsia, in a US urban, low-income multi-ethnic population.

Methods: This study, from the Boston Birth Cohort, included 980 women with term delivery, 79 with medically indicated PTD (mPTD) and preeclampsia, 52 with mPTD only, and 219 with spontaneous PTD (sPTD). Metabolomic profiling in postpartum plasma was conducted by liquid chromatography-mass spectrometry. Linear regression models were used to assess the associations of each metabolite with mPTD with preeclampsia, mPTD only, and sPTD, respectively, adjusting for pertinent covariates. Weighted gene coexpression network analysis was applied to investigate interconnected metabolites associated with the PTD/preeclampsia subgroups. Bonferroni correction was applied to account for multiple testing.

Results: A total of 380 known metabolites were analyzed. Compared to term controls, women with mPTD and preeclampsia showed a significant increase in 36 metabolites, mainly representing acylcarnitines and multiple classes of lipids (diacylglycerols, triacylglycerols, phosphocholines, and lysophosphocholines), as well as a decrease in 11 metabolites including nucleotides, steroids, and cholesteryl esters (CEs) (P < 1.3 × 10). Alterations of diacylglycerols, triacylglycerols, and CEs in women with mPTD and preeclampsia remained significant when compared to women with mPTD only. In contrast, the metabolite differences between women with mPTD only and term controls were only seen in phosphatidylethanolamine class. Women with sPTD had significantly different levels of 16 metabolites mainly in amino acid, nucleotide, and steroid classes compared to term controls, of which, anthranilic acid, bilirubin, and steroids also had shared associations in women with mPTD and preeclampsia.

Conclusion: In this sample of US high-risk women, PTD/preeclampsia subgroups each showed some unique and shared associations with maternal postpartum plasma metabolites, including those known to be predictors of future CVD. These findings, if validated, may provide new insight into metabolomic alterations underlying clinically observed PTD/preeclampsia subgroups and implications for women's future cardiometabolic health.
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http://dx.doi.org/10.1186/s12916-020-01741-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552364PMC
October 2020

Special issue on COVID-19 and pregnancy: Consequences for maternal and neonatal health.

Am J Reprod Immunol 2020 11;84(5):e13354

Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

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http://dx.doi.org/10.1111/aji.13354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536926PMC
November 2020

COVID-19 in pregnancy: Placental and neonatal involvement.

Am J Reprod Immunol 2020 11 15;84(5):e13306. Epub 2020 Aug 15.

Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 12 million infections and more than 550 000 deaths. Morbidity and mortality appear partly due to host inflammatory response. Despite rapid, global research, the effect of SARS-CoV-2 on the developing fetus remains unclear. Case reports indicate that vertical transmission is uncommon; however, there is evidence that placental and fetal infection can occur. Placentas from infected patients show inflammatory, thrombotic, and vascular changes that have been found in other inflammatory conditions. This suggests that the inflammatory nature of SARS-CoV-2 infection during pregnancy could cause adverse obstetric and neonatal events. Exposure to intrauterine inflammation and placental changes could also potentially result in long-term, multisystemic defects in exposed infants. This review will summarize the known literature on the placenta in SARS-CoV-2 infection, evidence of vertical transmission, and possible outcomes of prenatal exposure to the virus.
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http://dx.doi.org/10.1111/aji.13306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404599PMC
November 2020

Melatonin for prevention of fetal lung injury associated with intrauterine inflammation and for improvement of lung maturation.

J Pineal Res 2020 Oct 14;69(3):e12687. Epub 2020 Aug 14.

Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Inflammation is associated with injury to immature lungs, and melatonin administration to preterm newborns with acute respiratory distress improves pulmonary outcomes. We hypothesized that maternally administered melatonin may reduce inflammation, oxidative stress, and structural injury in fetal lung and help fetal lung maturation in a mouse model of intrauterine inflammation (IUI). Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). Pro-inflammatory cytokines, components of the Hippo pathway, and Yap1/Taz were analyzed in the fetal lung at E18 by real-time RT-qPCR. Confirmatory histochemistry and immunohistochemical analyses (surfactant protein B, vimentin, HIF-1β, and CXCR2) were performed. The gene expression of IL1β in the fetal lung was significantly increased in L compared to C, M, and ML. Taz expression was significantly decreased in L compared to C and M. Taz gene expression in L was significantly decreased compared with those in ML. Immunohistochemical analyses showed that the expression of HIF-1β and CXCR2 was significantly increased in L compared to C, M, and ML. The area of surfactant protein B and vimentin were significantly decreased in L than C, M, or ML in the fetal and neonatal lung. Antenatal maternally administered melatonin appears to prevent fetal lung injury induced by IUI and to help lung maturation. The results from this study results suggest that melatonin could serve as a novel safe preventive and/or therapeutic medicine for preventing fetal lung injury from IUI and for improving lung maturation in prematurity.
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http://dx.doi.org/10.1111/jpi.12687DOI Listing
October 2020

Genome-wide association study identifies a novel maternal gene × stress interaction associated with spontaneous preterm birth.

Pediatr Res 2021 May 29;89(6):1549-1556. Epub 2020 Jul 29.

Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Maternal stress is potentially a modifiable risk factor for spontaneous preterm birth (sPTB). However, epidemiologic findings on the maternal stress-sPTB relationship have been inconsistent.

Methods: To investigate whether the maternal stress-sPTB associations may be modified by genetic susceptibility, we performed genome-wide gene × stress interaction analyses in 1490 African-American women from the Boston Birth cohort who delivered term (n = 1033) or preterm (n = 457) infants. Genotyping was performed using Illumina HumanOmni 2.5 array. Replication was performed using data from the NICHD genomic and Proteomic Network (GPN) for PTB research.

Results: rs35331017, a T-allele insertion/deletion polymorphism in the protein-tyrosine phosphatase receptor Type D (PTPRD) gene, was the top hit that interacted significantly with maternal lifetime stress on risk of sPTB (P = 4.7 × 10). We revealed a dose-responsive association between degree of stress and risk of sPTB in mothers carrying the insertion/insertion genotype, but an inverse association was observed in mothers carrying the heterozygous or deletion/deletion genotypes. This interaction was replicated in African-American (P = 0.088) and Caucasian mothers (P = 0.023) from the GPN study.

Conclusion: We demonstrated a significant maternal PTPRD × stress interaction on sPTB risk. This finding, if further confirmed, may provide new insight into individual susceptibility to stress-induced sPTB.

Impact: This was the first preterm study to demonstrate a significant genome-wide gene-stress interaction in African Americans, specifically, PTPRD gene variants can interact with maternal perceived stress to affect risk of spontaneous preterm birth. The PTPRD × maternal stress interaction was demonstrated in African Americans and replicated in both African Americans and Caucasians from the GPN study. Our findings highlight the importance of considering genetic susceptibility in assessing the role of maternal stress on spontaneous preterm birth.
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http://dx.doi.org/10.1038/s41390-020-1093-1DOI Listing
May 2021

The role of in utero endotoxin exposure in the development of inflammatory bowel disease in mice.

Am J Reprod Immunol 2020 10 4;84(4):e13302. Epub 2020 Aug 4.

Department of Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Problem: Although early environmental influences are thought to influence the development of inflammatory bowel disease (IBD), little is known about the role of the in utero environment on subsequent IBD risk. We hypothesized that prenatal exposure to bacterial lipopolysaccharide (LPS) could modify the subsequent development of dextran sulfate sodium (DSS)-induced ulcerative colitis in adulthood by influencing the associated cellular and immune response.

Method Of Study: To test this hypothesis, we exposed developing mice in utero to LPS or saline (PBS) at E17.5, and then induced colitis at 5 weeks. We then assessed colitis severity and effects on the microbiome. In order to define the developmental impact of any potential LPS effect, we also exposed 1-week-old mice to either LPS or saline before inducing colitis at 5 weeks.

Results: Mice that had been exposed to LPS but not saline in utero were protected from subsequent colitis development, and their intestinal barrier integrity and tight junction expression distribution were similar to that of control mice that were not exposed to DSS. By contrast, mice exposed to either LPS or saline at day 7 of life all developed severe colitis upon subsequent DSS exposure.

Conclusion: These results identify an informative time window during fetal development during which exposure to an otherwise pro-inflammatory agent like LPS protects against an inflammatory disease in adulthood.
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http://dx.doi.org/10.1111/aji.13302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722031PMC
October 2020

Correction: The orphan nuclear receptor Nr4a1 mediates perinatal neuroinflammation in a murine model of preterm labor.

Cell Death Dis 2020 Jun 30;11(6):495. Epub 2020 Jun 30.

Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, WA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41419-020-2682-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327040PMC
June 2020

Predictors and reproducibility of urinary organophosphate ester metabolite concentrations during pregnancy and associations with birth outcomes in an urban population.

Environ Health 2020 05 24;19(1):55. Epub 2020 May 24.

Department of Environmental Health and Engineering, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe Street, Room W7513A, Baltimore, MD, 21205, USA.

Background: Organophosphate esters (OPEs) are synthetic chemicals used as flame retardants and plasticizers in a variety of goods. Despite ubiquitous human exposures and laboratory evidence that prenatal OPE exposures may disrupt offspring metabolism, perinatal studies of OPE health effects are limited. The objectives of this study were to: 1) Determine predictors and reproducibility of urinary OPE biomarker concentrations during pregnancy, and 2) Estimate the relation of prenatal OPE exposures with birth outcomes and cord blood adipokine and insulin concentrations.

Methods: We analyzed five OPE metabolites in urine samples collected at up to three visits during pregnancy from 90 women enrolled in the ORigins of Child Health And Resilience in Development (ORCHARD) pregnancy cohort in Baltimore, MD from 2017 to 2019. To quantify the variability of metabolite concentrations during pregnancy, we calculated intraclass correlation coefficients (ICCs) for each metabolite using mixed effects regression models. Using self-reported questionnaire data collected during gestation, we assessed possible sociodemographic and environmental/behavioral predictors of each OPE metabolite using generalized estimating equations to account for repeated exposure measures. We ascertained birth outcomes of 76 offspring from medical records, including weight-for-gestational age, length, ponderal index, and gestational age. In a subset of 37 infants, we measured cord blood concentrations of leptin, adiponectin, and insulin. To account for repeated exposure measures, we used linear structural equation models to assess the relations of standard deviation (SD) increases in prenatal OPE metabolite factor scores with continuous birth outcomes and cord blood biomarker concentrations.

Results: ICCs ranged from 0.09 for isopropylphenyl-phenyl phosphate (ip-PPP) to 0.59 for bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We observed little consistency in environmental or behavioral predictors of OPE exposures, although concentrations were generally lower for samples collected in the afternoon compared to morning and winter compared to other seasons. In adjusted analyses, a SD increase in BDCIPP concentration was associated with a 0.06 g/cm (95% CI: 0.00, 0.12) greater ponderal index. A SD increase in BDCIPP was associated with a 0.37 (95% CI: - 0.62, - 0.13) SD lower insulin concentration and 0.24 (95% CI: - 0.39, - 0.08) SD lower leptin concentration. Other OPEs were not associated with infant outcomes.

Conclusions: These findings suggest some OPEs may be metabolic disruptors warranting investigation in larger studies.
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http://dx.doi.org/10.1186/s12940-020-00610-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247187PMC
May 2020

Lower foetal haemoglobin levels at 31- and 34-weeks post menstrual age is associated with the development of retinopathy of prematurity : PacIFiHER Report No. 1 PacIFiHER Study Group (Preterm Infants and Fetal Haemoglobin in ROP).

Eye (Lond) 2021 02 14;35(2):659-664. Epub 2020 May 14.

Retina Division, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background/objectives: Previous studies have suggested that lower mean foetal haemoglobin (HbF) levels is associated with an increased risk for developing retinopathy of prematurity (ROP). Lower HbF levels may lead to high oxygen exposure to the developing retina thereby increasing the risk of acute ROP. In this study, we characterize the temporal relationship of HbF levels and the development of ROP.

Subjects/methods: This is a single institution prospective observational cohort study. Preterm infants (born <31 weeks gestational age or <1500 g) with HbF measured at birth (cord blood), 31-, 34-, and 37-weeks post menstrual age (PMA); and at least one ROP exam, were enrolled.

Results: A total of 60 preterm infants (28 females, 47%) were enrolled. At 31-, 34-, 37-weeks PMA, infants with ROP (mild = Type 2 or less severe and severe = Type 1 ROP) had statistically lower percentages of HbF than infants with no ROP (28.2 ± 15 and 9.7 ± 2.9 vs 67.1 ± 29.6; p < 0.0001; 23.3 ± 14.7 and 32.5 vs 60.1 ± 25; p < 0.005; 31.9 ± 15.8 and 41.6 vs 60.2 ± 20.0; p < 0.0019). Infants with HbF levels in the lowest tercile at 31-weeks PMA were 7.6 times more likely to develop mild and severe ROP (95% CI 2.1-24.0, p value = 0.0006) and this risk increased to 12.3 times (95% CI: 2.6-59.0, p value = 0.0017) at 34-weeks PMA.

Conclusions: Low HbF levels at 31- and 34-weeks PMA are associated with significantly increased risk of developing ROP. The decrease in HbF precedes the development of ROP and may be important in its pathogenesis.
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http://dx.doi.org/10.1038/s41433-020-0938-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027597PMC
February 2021

Is there a definite relationship between placental mTOR signaling and fetal growth?

Biol Reprod 2020 08;103(3):471-486

Reproductive Medical Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi Province, China.

Fetal growth restriction and overgrowth are common obstetrical complications that result in adverse perinatal outcomes and long-term health risks later in life, including neurodevelopmental dysfunction and adult metabolic syndrome. The placenta plays a critical role in the nutrition transfer from mother to fetus and even exerts adaptive mechanism when the fetus is under poor developmental conditions. The mammalian/mechanistic target of rapamycin (mTOR) signaling serves as a critical hub of cell growth, survival, and metabolism in response to nutrients, growth factors, energy, and stress signals. Placental mTOR signaling regulates placental function, including oxygen and nutrient transport. Therefore, placental mTOR signaling is hypothesized to have a positive relationship with fetal growth. In this review, we summarize that most studies support the current evidence that there is connection between placental mTOR signaling and abnormal fetal growth; however, but more studies should be performed following a vigorous and unanimous method for assessment to determine placental mTOR activity.
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http://dx.doi.org/10.1093/biolre/ioaa070DOI Listing
August 2020

Maternal azithromycin therapy for Ureaplasma parvum intraamniotic infection improves fetal hemodynamics in a nonhuman primate model.

Am J Obstet Gynecol 2020 10 25;223(4):578.e1-578.e11. Epub 2020 Apr 25.

Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Ureaplasma parvum infection is a prevalent cause of intrauterine infection associated with preterm birth, preterm premature rupture of membranes, fetal inflammatory response syndrome, and adverse postnatal sequelae. Elucidation of diagnostic and treatment strategies for infection-associated preterm labor may improve perinatal and long-term outcomes for these cases.

Objective: This study assessed the effect of intraamniotic Ureaplasma infection on fetal hemodynamic and cardiac function and the effect of maternal antibiotic treatment on these outcomes.

Study Design: Chronically catheterized pregnant rhesus monkeys were assigned to control (n=6), intraamniotic inoculation with Ureaplasma parvum (10 colony-forming units/mL, n=15), and intraamniotic infection plus azithromycin treatment (12.5 mg/kg twice a day intravenously, n=8) groups. At approximately 135 days' gestation (term=165 days), pulsed and color Doppler ultrasonography was used to obtain measurements of fetal hemodynamics (pulsatility index of umbilical artery, ductus venosus, descending aorta, ductus arteriosus, aortic isthmus, right pulmonary artery, middle cerebral artery and cerebroplacental ratio, and left and right ventricular cardiac outputs) and cardiac function (ratio of peak early vs late transmitral flow velocity [marker of ventricular function], Tei index [myocardial performance index]). These indices were stratified by amniotic fluid proinflammatory mediator levels and cardiac histology.

Results: Umbilical and fetal pulmonary artery vascular impedances were significantly increased in animals from the intraamniotic inoculation with Ureaplasma parvum group (P<.05). Azithromycin treatment restored values to control levels. Amniotic fluid prostaglandin F2 alpha levels were significantly higher in animals with abnormal umbilical artery pulsatility index (>1.1) than in those with normal blood flow (P<.05; Spearman ρ=0.6, P<.05). In the intraamniotic inoculation with Ureaplasma parvum group, left ventricular cardiac output was significantly decreased (P<.001), and more animals had abnormal right-to-left ventricular cardiac output ratios (defined as >1.6, P<.05). Amniotic fluid interleukin-6 concentrations were elevated in cases of abnormal right-to-left ventricular cardiac output ratios compared with those in normal cases (P<.05).

Conclusion: Fetal hemodynamic alterations were associated with intraamniotic Ureaplasma infection and ameliorated after maternal antibiotic treatment. Doppler ultrasonographic measurements merit continuing investigation as a diagnostic method to identify fetal cardiovascular and hemodynamic compromise associated with intrauterine infection or inflammation and in the evaluation of therapeutic interventions or clinical management of preterm labor.
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http://dx.doi.org/10.1016/j.ajog.2020.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591241PMC
October 2020

The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain.

Dev Neurobiol 2020 05 3;80(5-6):149-159. Epub 2020 Jun 3.

Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Fetuses exposed to an inflammatory environment are predisposed to long-term adverse neurological outcomes. However, the mechanism by which intrauterine inflammation (IUI) is responsible for abnormal fetal brain development is not fully understood. The mechanistic target of rapamycin (mTOR) signaling pathway is closely associated with fetal brain development. We hypothesized that mTOR signaling might be involved in fetal brain injury and malformation when fetuses are exposed to the IUI environment. A well-established IUI model was utilized by intrauterine injection of lipopolysaccharide (LPS) to explore the effect of IUI on mTOR signaling in mouse fetal brains. We found that microglia activation in LPS fetal brains was increased, as demonstrated by elevated Iba-1 protein level and immunofluorescence density. LPS fetal brains also showed reduced neuronal cell counts, decreased cell proliferation demonstrated by low Ki67-positive density, and elevated neuron apoptosis evidenced by high expression of cleaved Caspase 3. Furthermore, we found that mTOR signaling in LPS fetal brains was elevated at 2 hr after LPS treatment, declined at 6 hr and showed overall inhibition at 24 hr. In summary, our study revealed that LPS-induced IUI leads to increased activation of microglia cells, neuronal damage, and dynamic alterations in mTOR signaling in the mouse fetal brain. Our findings indicate that abnormal changes in mTOR signaling may underlie the development of future neurological complications in offspring exposed to prenatal IUI.
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http://dx.doi.org/10.1002/dneu.22755DOI Listing
May 2020

Fetal CHD and perinatal outcomes.

Cardiol Young 2020 May 20;30(5):686-691. Epub 2020 Apr 20.

Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Objective: To evaluate delivery management and outcomes in fetuses prenatally diagnosed with CHD.

Study Design: A retrospective cohort study was conducted on 6194 fetuses (born between 2013 and 2016), comparing prenatally diagnosed with CHD (170) to those with non-cardiac (234) and no anomalies (5790). Primary outcomes included the incidence of preterm delivery and mode of delivery.

Results: Gestational age at delivery was significantly lower between the CHD and non-anomalous cohorts (38.6 and 39.1 weeks, respectively). Neonates with CHD had a significantly lower birth weights (p < 0.001). There was an approximately 1.5-fold increase in the rate of primary cesarean sections associated with prenatally diagnosed CHD with an odds ratio of 1.49 (95% CI 1.06-2.10).

Conclusions: Our study provides additional evidence that the prenatal diagnosis of CHD is associated with a lower birth weight, preterm delivery, and with an increased risk of delivery by primary cesarean section.
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http://dx.doi.org/10.1017/S1047951120000785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780156PMC
May 2020

Dose-dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy.

Am J Reprod Immunol 2020 07 22;84(1):e13248. Epub 2020 May 22.

Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Problem: Systemic maternal inflammation is associated with adverse neonatal sequelae. We tested the hypothesis that IL-1β is a key inflammatory regulator of adverse pregnancy outcomes.

Method Of Study: Pregnant mice were treated with intraperitoneal injections of IL-1β (0, 0.1, 0.5, or 1 μg) from embryonic day (E)14 to E17. Placenta and fetal brains were harvested and analyzed for morphologic changes and IL-1β signaling markers.

Results: As compared with non-treated dams, maternal injections with IL-1β resulted in increased p-NF-κB and caspase-1 in placentas and fetal brains, but not consistently in spleens, suggesting induction of intrinsic IL-1β production. These findings were confirmed by increased levels of IL-1β in the placentas of the IL-1β-treated dams. Systemic treatment of dams with IL-1β suppressed Stat1 signaling. Maternal inflammation caused by IL-1β treatment reduced fetal viability to 80.6% and 58.9%, in dams treated with either 0.5 or 1 μg of IL-1β, respectively. In the placentas, there was an IL-1β dose-dependent distortion of the labyrinth structure, decreased numbers of mononuclear trophoblast giant cells, and reduced proportions of endothelial cells as compared to placentas from control dams. In fetal brains collected at E17, there was an IL-1β dose-dependent reduction in cortical neuronal morphology.

Conclusion: This work demonstrates that systemic IL-1β injection causes dose-dependent structural and functional changes in the placenta and fetal brain.
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http://dx.doi.org/10.1111/aji.13248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172143PMC
July 2020

Diffusion MRI revealed altered inter-hippocampal projections in the mouse brain after intrauterine inflammation.

Brain Imaging Behav 2020 Apr;14(2):383-395

Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Diffusion MRI (dMRI) is commonly used to map large axonal pathways in the white matter. Recent technical advances have also enabled dMRI to resolve the small and complex axonal and dendritic projections in the gray matter. This study investigated whether high-resolution dMRI can resolve the hippocampal neuronal projections and detect abnormal connections due to neurological injury. We performed 3D high spatial and angular resolution dMRI of the mouse brains of the offspring survivors from a model of intrauterine (UI) inflammation, who had known functional deficiency in the hippocampus. We used a novel hippocampal connection mapping method to quantify the intra- and inter-hippocampal projections among 34 automatically segmented hippocampal sub-regions. The results demonstrated wide-spread intra-hippocampal projections, but rather specific intra-hippocampal projections that primarily connected through the CA3 region. Compared with the control group (n = 9), UI-injured mice (n = 11) exhibited significantly reduced inter-hippocampal projection strength (p < 0.01), which correlated well with the neurobehavioral assessments (R = 0.47). Furthermore, using a whole-brain fixel-based analysis, we identified reduced fiber-density in the CA3 and the ventral hippocampal commissure of the UI-injured mice, which may explain the reduced inter-hippocampal projections. Histological findings also indicated reduced commissural fibers due to the UI-injury. Our study suggested that the dMRI-based connectivity mapping technique can potentially characterize abnormal hippocampal projections in neurological disorders.
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http://dx.doi.org/10.1007/s11682-019-00246-wDOI Listing
April 2020

Significance of abnormal umbilical artery Doppler studies in normally grown fetuses.

Matern Health Neonatol Perinatol 2020 20;6. Epub 2020 Feb 20.

Department of Gynecology and Obstetrics, Johns Hopkins University, School of Medicine, 600 N Wolfe St, Phipps 228, Baltimore, MD 21287 USA.

Objective: To determine whether there is a relationship between abnormal umbilical artery Doppler studies (UADS) and small for gestational age (SGA) birth weight and other adverse perinatal outcomes in fetuses that appear normally grown by ultrasound.

Methods: This was a retrospective study of all women who had UADS performed at or after 26 weeks of gestation at our institution between January 2005 and December 2012. Women were excluded if they had a fetal demise, a fetus with growth restriction, a fetus with congenital anomaly, or a multiple gestation. Women with missing delivery outcomes were excluded. The primary outcome was birth weight below the 10th percentile.

Results: There were 2744 women included in the study. Of those, 98 (3.6%) had an abnormal UADS, and 379 (13.8%) had an SGA neonate. Of the 2646 women who had a normal UADS, 353 (13.3%) women had an SGA neonate. Twenty-six (26.5%) of the 98 women who had an abnormal UADS had an SGA neonate. After adjusting for potential confounders, the adjusted odds ratio for an SGA neonate with an abnormal UADS was 2.2 (95% CI, 1.38-3.58;  <  0.05). In examining other adverse perinatal outcomes, neonatal intensive care unit (NICU) admission and low 5-min Apgar scores were 12.4 and 2.3%, respectively. The adjusted odds ratio for NICU admission was 1.84 (95% CI, 1.06-3.21;  <  0.05). Abnormal UADS was not associated with low Apgar scores (aOR 1.39: 95% CI 0.47-4.07;  > 0.05).

Conclusions: Our data suggest that abnormal UADS in fetuses that appear normally grown by ultrasound are associated with SGA neonates and NICU admission.
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http://dx.doi.org/10.1186/s40748-020-0115-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033920PMC
February 2020

Mouse Bone Marrow-Derived Mesenchymal Stem Cells Alleviate Perinatal Brain Injury Via a CD8 T Cell Mechanism in a Model of Intrauterine Inflammation.

Reprod Sci 2020 07 29;27(7):1465-1476. Epub 2020 Jan 29.

Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

The objective of this study was to determine if mouse bone marrow-derived mesenchymal stem cells (BMMSCs) ameliorate preterm birth and perinatal brain injury induced by intrauterine inflammation (IUI). A mouse model of IUI-induced perinatal brain injury at embryonic (E) day 17 was utilized. BMMSCs were derived from GFP-transgenic mice and phenotypically confirmed to be CD44, Sca-1, CD45, CD34, CD11b, and CD11c by flow cytometry and sorted by fluorescence-activated cell sorting (FACS). Dams were assigned to four groups: phosphate-buffered saline (PBS) + PBS, PBS + BMMSCs, lipopolysaccharide (LPS) + PBS, and LPS + BMMSCs. Following maternal IUI, there was a significant increase in CD8 T cells in the placentas. Maternally administered BMMSCs trafficked to the fetal side of the placenta and resulted in significantly decreased placental CD8 T cells. Furthermore, fetal trafficking of maternally administered BMMSCs correlated with an improved performance on offspring neurobehavioral testing in LPS + BMMSC group compared with LPS + PBS group. Our data support that maternal administration of BMMSCs can alleviate perinatal inflammation-induced brain injury and improve neurobehavioral outcomes in the offspring via CD8 T cell immunomodulation at the feto-placental interface.
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http://dx.doi.org/10.1007/s43032-020-00157-yDOI Listing
July 2020

The orphan nuclear receptor Nr4a1 mediates perinatal neuroinflammation in a murine model of preterm labor.

Cell Death Dis 2020 01 6;11(1):11. Epub 2020 Jan 6.

Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, WA, USA.

Prematurity is associated with perinatal neuroinflammation and injury. Screening for genetic modulators in an LPS murine model of preterm birth revealed the upregulation of Nr4a1, an orphan nuclear transcription factor that is normally absent or limited in embryonic brains. Concurrently, Nr4a1 was downregulated with magnesium sulfate (MgSO) and betamethasone (BMTZ) treatments administered to LPS exposed dams. To understand the role of Nr4a1 in perinatal brain injury, we compared the preterm neuroinflammatory response in Nr4a1 knockout (KO) versus wild type (wt) mice. Key inflammatory factors Il1b, Il6 and Tnf, and Iba1+ microglia were significantly lower in Nr4a1 KO versus wt brains exposed to LPS in utero. Treatment with MgSO/BMTZ mitigated the neuroinflammatory process in wt but not Nr4a1 KO brains. These results correspond with a reduction in cerebral hemorrhage in wt but not mutant embryos from dams given MgSO/BMTZ. Further analysis with Nr4a1-GFP-Cre × tdTomato loxP reporter mice revealed that the upregulation of Nr4a1 with perinatal neuroinflammation occurs in the cerebral vasculature. Altogether, this study implicates Nr4a1 in the developing vasculature as a potent mediator of neuroinflammatory brain injury that occurs with preterm birth. It is also possible that MgSO/BMTZ mitigates this process by direct or indirect inhibition of Nr4a1.
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http://dx.doi.org/10.1038/s41419-019-2196-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944691PMC
January 2020
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