Placental Inflammation Research Articles

IL-1 Blockade Mitigates Autism and Cerebral Palsy Traits in Offspring In-Utero Exposed to Group B Streptococcus Chorioamnionitis

Group B Streptococcus (GBS) is one of the most common bacteria responsible for placental and neonatal infection and inflammation resulting in lifelong neurobehavioral impairments. In particular, GBS-induced chorioamnionitis is known in preclinical models to upregulate inflammatory pathways, primarily through the activation of the interleukin-1 (IL-1) pathway, leading to brain injury and subsequent neurodevelopmental issues. Previous studies from our laboratory using Lewis rat pups have shown that male offspring exposed in utero to GBS chorioamnionitis develop brain injuries leading to neurobehavioral impairments such as autistic traits. In the present study, we aimed to explore whether blocking the IL-1 pathway could prevent or mitigate these neurodevelopmental impairments in adulthood. Using our established preclinical model, we administered IL-1 receptor antagonist (IL-1Ra) to dams with GBS-induced chorioamnionitis. Here, we show that IL-1Ra administration to dams reversed autistic and cerebral palsy traits in male adult offspring exposed in utero to GBS. Hence, IL-1 blockade could serve as a therapeutic intervention against pathogen-induced neurodevelopmental disorders. This research supports the need for future human randomized controlled trials to assess IL-1 blockade administered during pregnancy or in newborns as a strategy to reduce the long-term neurobehavioral consequences of prenatal infections, such as autism, cerebral palsy, learning disabilities, and other neurodevelopmental disorders.

Homeostatic Macrophages Prevent Preterm Birth and Improve Neonatal Outcomes by Mitigating In Utero Sterile Inflammation in Mice.

Preterm birth (PTB), often preceded by preterm labor, is a major cause of neonatal morbidity and mortality worldwide. Most PTB cases involve intra-amniotic inflammation without detectable microorganisms, termed in utero sterile inflammation, for which there is no established treatment. In this study, we propose homeostatic macrophages to prevent PTB and adverse neonatal outcomes caused by in utero sterile inflammation. Single-cell atlases of the maternal-fetal interface revealed that homeostatic maternal macrophages are reduced with human labor. M2 macrophage treatment prevented PTB and reduced adverse neonatal outcomes in mice with in utero sterile inflammation. Specifically, M2 macrophages halted premature labor by suppressing inflammatory responses in the amniotic cavity, including inflammasome activation, and mitigated placental and offspring lung inflammation. Moreover, M2 macrophages boosted gut inflammation in neonates and improved their ability to fight systemic bacterial infections. Our findings show that M2 macrophages are a promising strategy to mitigate PTB and improve neonatal outcomes resulting from in utero sterile inflammation.

Unravelling key genes associated with ovine Brucellosis by differential gene expression analysis: A holistic bioinformatics study

Ovine Brucellosis, caused by Brucella ovis bacteria, is a pathognomonic reproductive infectious disease of sheep that causes epididymitis in rams (male sheep) and placental inflammation in ewes (female sheep) leading to reduced fertility. The specific molecular process that causes alterations in genome of sheep during brucellosis is not yet fully understood. This study aimed to identify key host genes associated with the pathogenesis of ovine brucellosis caused by B. ovis. The GSE35614 dataset containing six healthy and six Brucella ovis infected sample of rams in the chronic phase 2 was obtained from the NCBI GEO database to examine and detect any differences in gene expression (DEGs). Functional and pathway enrichment analyse of the DEGs were performed along with the construction of protein-protein interaction network. Next, functional modules and hub genes were clustered and identified respectively, using the MCODE plugin. As a result, a total of 316 differentially expresses genes were filtered according to the provided cut-off criteria. The enriched DEGs were related to extracellular matrix interaction, cell adhesion mediated by integrin, angiogenesis, and inflammatory response. Furthermore, the hub gene analysis resulted in five hub genes namely, FN1, FBN1, CDH1, CD44, and SPP1, were up-regulated during the infection which could lead to reproductive disorders in sheep. In conclusion, the DEGs, functional and pathways terms, along with hub genes identified in the current study can provide prospective targets for the early diagnosis and treatment of brucellosis and provide insight into the molecular mechanism underlying the alterations that occur during brucellosis in sheep.

Alteration in sB7-H4 Serum Levels and Placental Biomarker Expression after Therapeutic Plasma Exchange in Early-Onset Preeclampsia Patients

Therapeutic plasma exchange (TPE) is a widely used treatment for numerous diseases including pregnancy-related conditions. Our prior study on 20 early-onset preeclampsia patients undergoing TPE revealed a significant extension in pregnancy duration and reduced serum levels of sFlt-1, sFlt-1/PlGF, and sEndoglin. Here, we investigated the impact of TPE on serum sB7-H4, an immunological checkpoint molecule, and placental proteins (Flt-1, Eng, B7-H4, iNOS, TNF-α) in TPE-treated early-onset preeclampsia patients (N = 12, 23 + 2–28 + 5 weeks), conventionally treated counterparts (N = 12, 23 + 5–30 weeks), and gestational age-matched controls (N = 8, 22 + 4–31 + 6 weeks). Immunoblotting, ELISA, and co-immunohistochemistry were used for biomarker analysis, including placental inflammation factors (iNOS, TNF-α). The results showed that TPE extended pregnancy by a median of 6.5 days in this cohort of early-onset preeclampsia. Serum sB7-H4, sFlt-1, and sEndoglin levels decreased, along with reduced expression of their membrane-bound proteins in placental tissue upon TPE treatment. Moreover, TPE-treated patients displayed reduced placental inflammation compared to preeclampsia patients receiving standard-of-care treatment. In conclusion, TPE may improve pregnancy outcomes in early-onset preeclampsia by lowering circulating levels of sB7-H4, sFlt-1, and sEndoglin, as well as reducing placental inflammation. This translational approach holds promise for enhancing placental function and extending gestation in high-risk pregnancies including very preterm PE or HELLP cases.

Inhibition of BCAT1 expression improves recurrent miscarriage by regulating cellular dysfunction and inflammation of trophoblasts.

Sustained or chronic inflammation in the placenta can result in placental insufficiency, leading to adverse reproductive outcomes such as pregnancy loss. Branched-chain amino acid transaminase 1 (BCAT1) expresses in the placenta and is involved in the pathological inflammatory response, but its role in recurrent miscarriage (RM) has not been fully investigated. In the present study, we delved into the effects of BCAT1 on trophoblast inflammation induced by lipopolysaccharide (LPS) and a mouse model of pregnancy loss induced by LPS. In vitro, after the HTR-8/SVneo cells were treated with LPS and BCATc inhibitor 2 (a selective BCAT inhibitor), the cell apoptosis was verified by TUNEL assay, and the activity of caspase-3 and caspase-9 was detected. Real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence (IF) were used to determine the expression of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and inflammasomes (NLRP3 and ASC) in LPS-treated trophoblast cells. Western blot analysis was performed to verify the expression of phospho-IκBα (p-IκBα) in cells and NF-κB p65 in the nuclei. IF staining was used to detect the nuclear translocation of NF-κB p65. The DNA binding activity of NF-κB was detected by an electrophoretic mobility shift assay (EMSA). The results demonstrated that inhibition of BCAT1 reduced trophoblast apoptosis, suppressed the release of proinflammatory cytokines, and prevented NLRP3 inflammasome activation in response to LPS. Additionally, BCAT1 inhibition blocked the activation of the NF-κB pathway in trophoblasts. This study highlights the potential therapeutic role of targeting BCAT1 in preventing adverse reproductive outcomes associated with chronic placental inflammation.

1,25-Dihydroxyvitamin D3 protects against placental inflammation by suppressing NLRP3-mediated IL-1β production via Nrf2 signaling pathway in preeclampsia.

Maternal vitamin D deficiency is associated with an increased risk of preeclampsia, a potentially life-threatening multi-system disorder specific to human pregnancy. Placental trophoblast dysfunction is a key factor in the development of preeclampsia, and the activation of NOD-like receptor protein 3 (NLRP3) inflammasome may play a crucial role in this process. Previous studies have suggested that vitamin D can exert beneficial effects by suppressing inflammasome activation, but the underlying mechanism has not been fully elucidated. This study aims to explore the protective effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the placenta and to investigate the mechanisms by which 1,25(OH)2D3 attenuates NLRP3 inflammasome activation in a rat model of preeclampsia and hypoxia-cultured placental trophoblast cells. Our findings demonstrated that supplementation of rats with 1,25(OH)2D3 mitigated placental inflammation and prevented multi-organ dysfunction associated with preeclampsia. Treatment with 1,25(OH)2D3 inhibited inflammasome-mediated inflammation in trophoblast cells via its receptor VDR by reducing the expression of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), decreasing IL-1β production, reducing mitochondrial reactive oxygen species generation, and enhancing the expression and enzymatic activity of Cu/Zn-superoxide dismutase (SOD). Mechanistically, 1,25(OH)2D3 upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, subsequently suppressing NLRP3-mediated IL-1β overproduction in trophoblast cells. Our study indicates that 1,25(OH)2D3 inhibits NLRP3-mediated inflammation in trophoblast cells during preeclampsia by stimulating the Nrf2 signaling pathway and inhibiting oxidative stress.

Placental lesions in patients with antiphospholipid antibody syndrome: experience of a single tertiary-care Italian reference center

IntroductionAbnormal placentation contributes to obstetric morbidity in antiphospholipid antibodies syndrome (APS). The placenta is the main target of antiphospholipid antibodies (aPL) in obstetric APS and is the site of dysfunctional inflammatory responses and thrombosis. Standard treatment for APS during pregnancy includes low-dose aspirin (LDA) plus low molecular weight heparin (LMWH) and, in refractory cases, hydroxychloroquine (HCQ). Recently, a systematic review of the literature identified five main pathological placental lesions in APS patients: placental infarction, decidual vasculopathy, decidual inflammation, increase of syncytial knots due to syncytiotrophoblast death, and decrease in vasculosyncytial membranes. The aims of this study were to investigate whether placental lesions associate with obstetrical outcomes in a cohort of APS patients.Methods130 pregnant APS patients evaluated between 2009 and 2023 at the High-Risk Obstetrics Outpatient Clinic of San Raffaele Hospital, Milan, were enrolled. Placental samples from 25 spontaneously conceived pregnancies in APS patients were collected from January 2017 to May 2023 and analyzed.ResultsAll (n = 130) patients were on LDA and 110/130 (85%) on both LDA and LMWH. Twenty-six patients (20%) also received HCQ. In these patients, signs of placental inflammation (preterm birth and preterm premature rupture of membranes) were less frequently observed. Of the 25 placental samples analyzed, 19 (76%) patients had primary APS, while 6 patients had APS secondary to SLE. All patients were treated with LDA and LMWH. In patients with concomitant systemic lupus erythematosus (SLE) or in refractory APS, HCQ was added. Histological analysis of placental tissue revealed increased syncytial knots in 17/25 (68%) placentas, decreased vasculosyncytial membranes in 11/25 (44%), infarction in 8/25 (32%), presence of macrophages and decidual inflammation in 2/25 (8%), and atherosis or reduction of spiral artery remodeling in 3/25 (12%). We also observed at least two coexisting placental lesions in 12/25 (48%) placentas. In the placenta of patients treated with HCQ we did not observe any decidual inflammation at histology.ConclusionPlacental anomalies have occurred in patients with APS despite close and optimal obstetric monitoring. It is thus tempting to speculate that HCQ may have beneficial effects on pregnancy by decreasing the risk of deciduitis in patients with APS.

Microplastics caused embryonic growth retardation and placental dysfunction in pregnant mice by activating GRP78/IRE1α/JNK axis induced apoptosis and endoplasmic reticulum stress

Microplastics (MPs), a brand-new class of worldwide environmental pollutant, have received a lot of attention. MPs are consumed by both humans and animals through water, food chain and other ways, which may cause potential health risks. However, the effects of MPs on embryonic development, especially placental function, and its related mechanisms still need to be further studied. We investigated the impact on fetal development and placental physiological function of pregnant mice by consecutive gavages of MPs at 0, 25, 50, 100 mg/kg body weight during gestational days (GDs 0–14). The results showed that continuous exposure to high concentrations of MP significantly reduced daily weight gain and impaired reproductive performance of pregnant mice. In addition, MPs could significantly induce oxidative stress and placental dysfunction in pregnant mice. On the other hand, MPs exposure significantly decreased placental barrier function and induced placental inflammation. Specifically, MPs treatment significantly reduced the expression of tight junction proteins in placentas, accompanied by inflammatory cell infiltration and increased mRNA levels of pro-inflammatory cytokines and chemokines in placentas. Finally, we found that MPs induced placental apoptosis and endoplasmic reticulum (ER) stress through the GRP78/IRE1α/JNK axis, leading to placental dysfunction and decreased reproductive performance in pregnant mice. We revealed for the first time that the effects of MPs on placental dysfunction in pregnant animals. Blocking the targets of MPs mediated ER stress will provide potential therapeutic ideas for the toxic effects of MPs on maternal pregnancy.

In vitro and in vivo effects of Galectin-3 inhibitor TD139 on inflammation and ERK/JNK/p38 pathway in gestational diabetes mellitus.

This study aims to investigate the effects of the Galectin-3 (Gal-3) inhibitor TD139 on inflammation and the extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 pathway in gestational diabetes mellitus (GDM). Human placental tissues were treated with TD139 and TNF-α, assessing Gal-3, ERK/JNK/p38 activation, and inflammatory cytokines. GDM was induced in mice via subcutaneous injections of streptozotocin (STZ). After confirming GDM, mice were treated with 15 mg/kg TD139 on GD 10.5 12.5, 14.5, 16.5, and 18.5. Serum inflammatory cytokines were measured on GD 20.5, and post-delivery placental tissues were analyzed. Data were analyzed using one-way or two-way repeated measures ANOVA with post hoc tests. TD139 suppressed TNF-α-induced increases in Gal-3, IL-1β, IL-6, MCP-1, and ERK/JNK/p38 activation in placental tissues. In STZ-induced GDM mice, TD139 reduced glucose levels, weight loss, and food and water intake. TD139 significantly lowered TNF-α, IL-1β, IL-6, and MCP-1 in serum and placental tissues and inhibited the ERK/JNK/p38 pathway. TD139 improved pup numbers in GDM mice compared to untreated ones. TD139 reduces inflammation and inhibits the ERK/JNK/p38 pathway in TNF-α stimulated placental tissues and STZ-induced GDM mice, suggesting its therapeutic potential for managing GDM-related placental inflammation and improving pregnancy outcomes. The study used TNF-α to mimic GDM in placental tissues and an STZ-induced GDM mouse model, which may not fully represent human GDM complexity. Future research should explore alternative models, and broader signaling pathways, and thoroughly evaluate TD139's safety in pregnancy.

Associations of Placental Inflammation and Oxidative Stress Biomarkers with Glucolipid Metabolism in Children: A Birth Cohort Study in China.

The maternal intrauterine immune environment may affect offspring long-term health. We aimed to investigate the association between the intrauterine placental immunological milieu and glycolipid metabolic health in children. This study enrolled 1803 mother-child pairs from the Ma'anshan birth cohort (2013-2014). Placental mRNA expression of inflammatory cytokines (interleukin-1β [IL-1β], IL-10, monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-4, IL-6, IL-8, C-reactive protein, and interferon-γ) and oxidative stress biomarkers (heme oxygenase-1, hypoxia-inducible factor-1alpha, and glucose-related protein 78) was quantified using real-time quantitative polymerase chain reaction. Fasting blood glucose, insulin, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol were assessed at 5 to 6 years old. Statistical analyses included multiple linear regression, binary logistic regression, restricted cubic spline model, and the Bayesian kernel machine regression model. Placental inflammatory cytokines (IL-1β, monocyte chemoattractant protein-1, C-reactive protein, IL-6, IL-8, IL-10) and oxidative stress biomarkers (heme oxygenase-1, hypoxia-inducible factor-1alpha, glucose-related protein 78) showed positive associations with children's fasting blood glucose levels. Heme oxygenase-1 and glucose-related protein 78 exhibited negative correlations with children's fasting insulin levels. Elevated IL-6, heme oxygenase-1, hypoxia-inducible factor-1alpha, and glucose-related protein 78 were associated with increased risk of prediabetes in children. Overall upregulation of placental proinflammatory cytokines and oxidative stress factors mRNA expression correlated with higher prediabetes risk in children. Bayesian kernel machine regression analysis indicated a joint positive effect of the 12 placental inflammation and oxidative stress mixtures on children's risk of high fasting blood glucose. This exploratory study underscores significant correlations between maternal intrauterine placental inflammation, oxidative stress markers, and offspring fasting blood glucose and insulin levels. These findings highlight the potential role of intrauterine holistic immunity in shaping offspring glucose metabolism health.

Placental inflammation and early antecedents of health on risk of adverse pregnancy and offspring outcomes

Placental inflammation and early antecedents of health on risk of adverse pregnancy and offspring outcomes

Chronic gestational inflammation: Comparisons of obesity-mediated and preeclampsia-mediated placental inflammation using transcriptomic and histological methods

Chronic gestational inflammation: Comparisons of obesity-mediated and preeclampsia-mediated placental inflammation using transcriptomic and histological methods

Exogenous PD-L1 binds to PD-1 to alleviate and prevent autism-like behaviors in maternal immune activation-induced male offspring mice

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder caused by the interaction of multiple pathogenic factors. Epidemiological studies and animal experiments indicate that maternal immune activation (MIA) is closely related to the development of ASD in offspring. A large number of pro-inflammatory cytokines are transferred from the placenta to the fetal brain during MIA, which impedes fetal neurodevelopment and is accompanied by activation of immune cells and microglia. Programmed cell death protein 1 (PD-1) can be highly expressed on the surface of various activated immune cells, when combined with programmed cell death-ligand 1 (PD-L1), it can activate the PD-1/PD-L1 pathway and exert powerful immunosuppressive effects, suggesting that this immune checkpoint may have the potential to treat MIA-induced ASD. This study combined bioinformatics analysis and experimental validation to explore the efficacy of Fc-fused PD-L1 (PD-L1-Fc) in treating MIA-induced ASD. Bioinformatics analysis results showed that in human placental inflammation, IL-6 was upregulated, T cells proliferated significantly, and the PD-1/PD-L1 pathway was significantly enriched. The experimental results showed that intraperitoneal injection of poly(I:C) induced MIA in pregnant mice resulted in significant expression of IL-6 in their serum, placenta, and fetal brain. At the same time, the expression of PD-1 and PD-L1 in the placenta and fetal brain increased, CD4+ T cells in the spleen were significantly activated, and PD-1 expression increased. Their offspring mice exhibited typical ASD-like behaviors. In vitro experiments on primary microglia of offspring mice have confirmed that the expression of IL-6, PD-1, and PD-L1 is significantly increased, and PD-L1-Fc effectively reduced their expression levels. In the prefrontal cortex of MIA offspring mice, there was an increase in the expression of IL-6, PD-1, and PD-L1; activation of microglial cells, and colocalization with PD-1. Then we administered brain stereotaxic injections of PD-L1-Fc to MIA offspring mice and intraperitoneal injections to MIA pregnant mice. The results indicated that PD-L1-Fc effectively suppressed neuroinflammation in the frontal cortex of offspring mice and partially ameliorated ASD-like behaviors; MIA in pregnant mice was significantly alleviated, and the offspring mice they produced did not exhibit neuroinflammation or ASD-like behaviors. In summary, we have demonstrated the therapeutic ability of PD-L1-Fc for MIA-induced ASD, aiming to provide new strategies and insights for the treatment of ASD.

In Situ Analyses of Placental Inflammatory Response to SARS-CoV-2 Infection in Cases of Mother-Fetus Vertical Transmission.

It has been shown that vertical transmission of the SARS-CoV-2 strain is relatively rare, and there is still limited information on the specific impact of maternal SARS-CoV-2 infection on vertical transmission. The current study focuses on a transcriptomics analysis aimed at examining differences in gene expression between placentas from mother-newborn pairs affected by COVID-19 and those from unaffected controls. Additionally, it investigates the in situ expression of molecules involved in placental inflammation. The Papa Giovanni XXIII Hospital in Bergamo, Italy, has recorded three instances of intrauterine transmission of SARS-CoV-2. The first two cases occurred early in the pandemic and involved pregnant women in their third trimester who were diagnosed with SARS-CoV-2. The third case involved an asymptomatic woman in her second trimester with a twin pregnancy, who unfortunately delivered two stillborn fetuses due to the premature rupture of membranes. Transcriptomic analysis revealed significant differences in gene expression between the placentae of COVID-19-affected mother/newborn pairs and two matched controls. The infected and control placentae were matched for gestational age. According to the Benjamani-Hochberg method, 305 genes met the criterion of an adjusted p-value of less than 0.05, and 219 genes met the criterion of less than 0.01. Up-regulated genes involved in cell signaling (e.g., CCL20, C3, MARCO) and immune response (e.g., LILRA3, CXCL10, CD48, CD86, IL1RN, IL-18R1) suggest their potential role in the inflammatory response to SARS-CoV-2. RNAscope® technology, coupled with image analysis, was utilized to quantify the surface area covered by SARS-CoV-2, ACE2, IL-1β, IL-6, IL-8, IL-10, and TNF-α on both the maternal and fetal sides of the placenta. A non-statistically significant gradient for SARS-CoV-2 was observed, with a higher surface coverage on the fetal side (2.42 ± 3.71%) compared to the maternal side (0.74 ± 1.19%) of the placenta. Although not statistically significant, the surface area covered by ACE2 mRNA was higher on the maternal side (0.02 ± 0.04%) compared to the fetal side (0.01 ± 0.01%) of the placenta. IL-6 and IL-8 were more prevalent on the fetal side (0.03 ± 0.04% and 0.06 ± 0.08%, respectively) compared to the maternal side (0.02 ± 0.01% and 0.02 ± 0.02%, respectively). The mean surface areas of IL-1β and IL-10 were found to be equal on both the fetal (0.04 ± 0.04% and 0.01 ± 0.01%, respectively) and maternal sides of the placenta (0.04 ± 0.05% and 0.01 ± 0.01%, respectively). The mean surface area of TNF-α was found to be equal on both the fetal and maternal sides of the placenta (0.02 ± 0.02% and 0.02 ± 0.02%, respectively). On the maternal side, ACE-2 and all examined interleukins, but not TNF-α, exhibited an inverse mRNA amount compared to SARS-CoV-2. On the fetal side, ACE-2, IL-6 and IL-8 were inversely correlated with SARS-CoV-2 (r = -0.3, r = -0.1 and r = -0.4, respectively), while IL-1β and IL-10 showed positive correlations (r = 0.9, p = 0.005 and r = 0.5, respectively). TNF-α exhibited a positive correlation with SARS-CoV-2 on both maternal (r = 0.4) and fetal sides (r = 0.9) of the placenta. Further research is needed to evaluate the correlation between cell signaling and immune response genes in the placenta and the vertical transmission of SARS-CoV-2. Nonetheless, the current study extends our comprehension of the molecular and immunological factors involved in SARS-CoV-2 placental infection underlying maternal-fetal transmission.

Low-dose aspirin potentially mitigates placental inflammation by increasing LXA4 and decreasing NLRP3 in an in vitro model of preeclampsia

Low-dose aspirin potentially mitigates placental inflammation by increasing LXA4 and decreasing NLRP3 in an in vitro model of preeclampsia

Associations of Gestational Exposure to Air Pollution and Polycyclic Aromatic Hydrocarbons with Placental Inflammation.

Restricted fetal growth (RFG) is a leading contributor to perinatal mortality and has been associated with gestational exposure to air pollution, such as fine particulate matter (PM2.5), nitrogen dioxide (NO2), and polycyclic aromatic hydrocarbons (PAHs). This study examines the association between trimester-specific and weekly means of air pollution throughout gestation and placental inflammatory markers at delivery. In a prospective cohort study of 263 pregnant women in Rochester, NY, we measured interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in placental tissue and estimated gestational exposure to PM2.5 and NO2 using a high-resolution spatial-temporal model. Exposure to PAHs was estimated using urinary 1-hydroxypyrene (1-OHP) concentrations collected once per trimester. Using distributed lag models with a penalized spline function, each interquartile range (2.6 μg/m3) increase in PM2.5 concentration during gestational weeks 6-11 was associated with decreased placental IL-6 levels (-22.2%, 95% CI: -39.0%, -0.64%). Using multiple linear regression models, each interquartile range increase of 1-OHP was associated with an increase in TNF-α in the first trimester (58.5%, 95% CI: 20.7%, 74.2%), third trimester (22.9%, 95% CI: 0.04%, 49.5%), and entire pregnancy (29.6%, 95%CI: 3.9%,60.6%). Our results suggest gestational exposure to air pollution may alter the inflammatory environment of the placenta at delivery.

Medical termination of pregnancy with digoxin in a patient affected by severe congenital toxoplasmosis.

SynopsisIntrafetal digoxin is a safer and effective alternative to perform medical termination of pregnancy over intracardiac potassium chloride in cases of massive placental inflammation, such as congenital infections.

Transamniotic Stem Cell Therapy Modulates Uterine Natural Killer Cell Activity in the Hypoxia Model of Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR) pathophysiology is driven by abnormal uterine natural killer cell (uNK) activity leading to placental dysfunction. Transamniotic stem cell therapy (TRASCET) with mesenchymal stem cells (MSCs) can improve experimental IUGR by mechanisms not fully understood. We sought to examine TRASCET's effects in downstream products of uNKs in a model of IUGR: 15 Sprague-Dawley dams were exposed to alternating hypoxia (10.5% O2) from gestational day 15 (E15) until term (E21). Their fetuses (n = 189) were divided into four groups. One group remained untreated (n = 52), whereas three groups received volume-matched intraamniotic injections of either saline (sham, n = 44) or a suspension of amniotic fluid-derived MSCs, either in their native state (TRASCET, n = 50) or "primed" to an enhanced antiinflammatory phenotype (TRASCET-Primed, n = 43). Normal fetuses served as controls (n = 33). At term, various analyses were performed, including ELISA for surrogates of placental inflammation and uNK activity. Statistical comparisons included Bonferroni-adjusted criterion. Overall survival from hypoxia was 74% (140/189). Placental efficiency was lower in untreated and sham but normalized in both TRASCET groups (P < 0.01-0.47). Interleukin-17, a stimulator of uNKs, was elevated from normal in all groups (P < 0.01 for all). Interferon-gamma, released from activated uNKs, was elevated in all groups except sham but lower than the untreated in both TRASCET groups (P ≤ 0.01-0.06). Tumor necrosis factor-alpha, also produced by uNKs, was elevated in untreated and sham (P < 0.01 for both), but normalized by TRASCET (P = 0.05) and even lowered from normal in TRASCET-Primed (P < 0.01). Vascular endothelial growth factor, also released by uNKs, was elevated in untreated and sham but lower than normal in both TRASCET groups (P < 0.01 for all). We conclude that TRASCET with MSCs modulates the activity of placental uNKs in experimental IUGR, with distinct effects on their downstream products. This mechanistic insight may inform the development of novel strategies for the management of this disease.

P-787 Gestational diabetes in mice induces embryonic fibro-adipogenic progenitors memory that impedes the recovery of injured skeletal muscle in adult offspring

Abstract Study question Whether and how intrauterine hyperglycemia induced by Gestational diabetes steadily influences the function and fate of mesenchymal stem cells, specifically fibro-adipogenic progenitors. Summary answer Gestational diabetes in mice caused declines in self-renewal and paracrine in fibro-adipogenic progenitors, prompted adipogenesis and fibrosis, destroyed recovery after muscular injury in adult offspring. What is known already Gestational diabetes contributed to the increased susceptibility to metabolic disorders, cardiovascular diseases and atherosclerosis. Intrauterine hyperglycemia promoted placental inflammation and endowed the hematopoietic stem and progenitor cells. As an important mesenchymal stem cell, fibro-adipogenic progenitors (FAPs) play a key role in the process of “replace, repair, regeneration, restore and regress”. When acute injury happens to skeletal muscle, the fibro-adipogenic progenitors cluster start to renew itself and differentiate into functional cells like fibroblasts or adipocytes, secrete cytokines to nearby myoblasts, inducing myotube formation and muscle regeneration by cell-cell communication. Study design, size, duration Pregnant mice were randomly divided into control (CTR) and gestational diabetes (GDM) groups, GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while CTR group was treated with vehicle buffer. Only when random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. At 8 weeks of offspring, we intramuscular injected cardiotoxin (CTX) to induce acute tibialis anterior muscle injury. Participants/materials, setting, methods 7 days after CTX intramuscular injection (CTX-D7) in offspring, mice were sacrificed and tiabialis anterior muscle was selected. Perilipin immunochemical and immunofluorescent staining, MASSON and Sirius Red staining were used to evaluate the recovery extent between CTR and GDM groups. Then we used fluorescence-activated cell sorting to evaluate the self proliferation of fibro-adipogenic cells at CTX-D3. We also collected FAPs to perform induced differentiation in vitro, co-culture with myoblast and SMART-sequence to explore underlying mechanism. Main results and the role of chance 7 days after cardiotoxin injection (CTX-D7), we used WGA to mark injured myofibers, eMHC to mark regenerated myofibers. Immunofluorescence and hematoxylin-eosin staining showed the muscle fibers in GDM male were still severe damaged and inadequate recovered when compared to CTR group. Perilipin immunochemical staining demonstrated more lipids deposition in GDM male muscle. MASSON and Sirius Red staining also revealed increased accumulation of collagen fibers in GDM group. Fluorescence-activated cell sorting firstly displayed depletion in numbers of Lineage-VCAM-Sca-1+ fibro-adipogeneic progenitors (FAPs) compartment in GDM group at CTX-D3 compared to CTR group. Using α-SMA to mark collagen fibers, perilipin to mark adiposity cells, we also observed activation of the FAPs into fibrosis or adipogenesis by in vitro induced differentiation. Myotubes formation experiment showed that myotubes were thinner and fusion extent was worse in myoblasts co-cultured with GDM FAPs rather than CTR FAPs. Finally, we performed SMART-sequence of FAPs between groups. Regarding p &amp;lt; 0.05 and the absolute of log2 foldchange &amp;gt;1 as significance, we totally found 1572 down-regulated genes, 1527 up-regulated genes in GDM FAPs. And the GO term analysis showed us that WNT signaling pathway, cell surface receptor signaling pathway were most highly affected. Limitations, reasons for caution We haven’t found out the key molecule in WNT signaling pathway, and how intrauterine hyperglycemia steadily affected FAP’s function remains to be explored. Also, whether other mesenchymal stem cells are influenced by short-term intrauterine hyperglycemia needs to be clarified. Wider implications of the findings Fibro-adipogenic progenitors is an important part of mesenchymal stem cells. These results demonstrated GDM in mice might induce mesenchymal memory that affects the long-term health of the offspring, which reminds us the stemness of GDM progenitors or stem cells might be destroyed and its cell-cell function may be also damaged. Trial registration number ZJU20210047

Placental chronic inflammatory histopathology and fetal growth in a cohort with universal placental examination

IntroductionChronic placental inflammation is a routinely diagnosed group of placental lesions that reflect immunologic dysfunction of the mother, fetus, or both. MethodsComplete placental pathology examinations were performed for all term births at New York Presbyterian- Brooklyn Methodist Hospital from January 2010–August 2016. Diagnoses were blinded except to gestational age. CPI lesions were marked as chronic choriodeciduitis, decidual plasma cells, chronic inflammation of basal plate with anchoring villitis, and chronic villitis. ResultsIn this cohort of term pregnancies, 257 (11.6 %) males and 218 (9.8 %) females had ≥1 CPI lesions. Chronic villitis was the most common (319 or 14 %), with chronic choriodeciduitis, decidual plasma cells, and chronic inflammation of basal plate with anchoring villitis in 94 (4 %), 69 (3 %) and 170 (8 %), respectively. In males, chronic villitis was associated with lower gestational adjusted birthweight and had no association with placental weight. In females, chronic villitis was associated with lower gestational adjusted birthweight, but the effect became nonsignificant after adjustment for placental weight. DiscussionIn summary, CPI lesions’ incidence and association with birth weight vary by sex. Chronic villitis is associated with lower birthweight in females; this effect is completely mediated by placental weight. Chronic villitis showed a weak direct association of chronic villitis in males, but no association with lower placental weight in males. We suggest that differences between our results and previous publications reflect effects of sampling bias.