Mouse Model Of Intrauterine Inflammation Research Articles

Maternal siRNA silencing of placental SAA2 mitigates preterm birth following intrauterine inflammation.

The placental inflammatory processes induced maternally result in preterm birth (PTB). Serum amyloid A (SAA) is a well-known biomarker of inflammation. The objective of this study was to investigate whether murine placental SAA isoforms (SAA1–4) participate in the mechanism of spontaneous PTB and whether maternal regulation of SAA production may serve as a therapeutic approach. During the gestation, all isoforms of SAA were detectable except SAA2. The mouse model of intrauterine inflammation was established using LPS infusion to the uterus. Following intrauterine inflammation, placental SAA2 increased significantly. Inhibition of Saa2, using siSaa2, markedly decreased PTB. The increased placental expression of pro-inflammatory cytokines Il1β, Il6, and Tnfα were downregulated by siSaa2 treatment. Maternal inhibition of Saa2 did not change the expression of Saa1–4 in the fetal brain. Explant inflammatory culture of placentas with siSaa2 showed similar results to our in vivo experiments. This study demonstrates the highly expressed placental SAA2 as a novel therapeutic target, and maternal administration of siRNA as a promising approach to alleviate PTB.

Placental Macrophages Demonstrate Sex-Specific Response to Intrauterine Inflammation and May Serve as a Marker of Perinatal Neuroinflammation

Preterm birth (PTB) is considered to be one of the most frequent causes of neonatal death. Prompt and effective measures to predict adverse fetal outcome following PTB are urgently needed. Placenta macrophages are a critical immune cell population during pregnancy, phenotypically divided into M1 and M2 subsets. An established mouse model of intrauterine inflammation (IUI) was applied. Placenta (labyrinth) and corresponding fetal brain were harvested within 24 hours post injection (hpi). Flow cytometry, Western blot, real-time qPCR, and regular histology were utilized to examine the cytokines, macrophage polarization, and sex-specificity. Placental exposure to LPS led to significantly reduced labyrinth thickness compared to PBS-exposed controls as early as 3 hpi, accompanied by apoptosis and necrosis. Pro-inflammatory M1 markers, Il-1β, and iNOS, and anti-inflammatory M2 marker Il-10 increased significantly in placentas exposed to IUI. Analysis of flow cytometry revealed that fetal macrophages (Hofbauer cell, HBCs) were mostly M1-like and that maternal inter-labyrinth macrophages (MIM) were M2-like in their features in IUI. Male fetuses displayed significantly decreased M2-like features in HBCs at 3 and 6 hpi, while female fetuses showed significant increase in M2-like features in MIM at 3 and 6 hpi. Furthermore, there was a significant correlation between the frequency of HBCs and corresponding microglial marker expression at 3 and 6 hpi. Placental macrophages demonstrated sex-specific features in response to IUI. Specifically, HBCs may be a potential biomarker for fetal brain injury at preterm birth.

Intrauterine Inflammation Alters the Transcriptome and Metabolome in Placenta.

Placental insufficiency is implicated in spontaneous preterm birth (SPTB) associated with intrauterine inflammation. We hypothesized that intrauterine inflammation leads to deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy ultimately resulting in SPTB. Using a mouse model of intrauterine inflammation that leads to preterm delivery, we performed RNA-seq and metabolomics studies to assess how intrauterine inflammation alters gene expression and/or modulates metabolite production and abundance in the placenta. 1871 differentially expressed genes were identified in LPS-exposed placenta. Among them, 1,149 and 722 transcripts were increased and decreased, respectively. Ingenuity pathway analysis showed alterations in genes and canonical pathways critical for regulating oxidative stress, mitochondrial function, metabolisms of glucose and lipids, and vascular reactivity in LPS-exposed placenta. Many upstream regulators and master regulators important for nutrient-sensing and mitochondrial function were also altered in inflammation exposed placentae, including STAT1, HIF1α, mTOR, AMPK, and PPARα. Comprehensive quantification of metabolites demonstrated significant alterations in the glucose utilization, metabolisms of branched-chain amino acids, lipids, purine and pyrimidine, as well as carbon flow in TCA cycle in LPS-exposed placenta compared to control placenta. The transcriptome and metabolome were also integrated to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the placenta transcriptome and metabolome were identified in placentae exposed to intrauterine inflammation. Altered mitochondrial function and energy metabolism may underline the mechanisms of inflammation-induced placental dysfunction.

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

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.

The Absence of TLR4 Prevents Fetal Brain Injury in the Setting of Intrauterine Inflammation

BackgroundExposure to intrauterine inflammation during pregnancy is linked to brain injury and neurobehavioral disorders in affected children. Innate immunity, specifically Toll-like receptor (TLR) signaling pathways are present throughout the reproductive tract as well as in the placenta, fetal membranes, and fetus. The TLR pathways are mechanistically involved in host responses to foreign pathogens and may lead to brain injury associated with prenatal inflammation.ObjectiveWe aimed to determine whether the activation of the TLR4 signaling pathway, in the mother and fetus, is critical to fetal brain injury in the setting of intrauterine inflammation.MethodsA mini-laparotomy was performed on time pregnant C57B6 mice and 2 knockout mouse strains lacking the function of the Tlr4 and Myd88 genes on embryonic day 15. Intrauterine injections of Escherichia coli lipopolysaccharide or saline were administered as described previously. Dams were killed 6 hours postsurgery, and placental, amniotic fluid, and fetal brain tissue were collected. To assess brain injury, quantitative polymerase chain reaction (qPCR) analysis was performed on multiple components of the NOTCH signaling pathway, including Hes genes. Interleukin (IL) IL6, IL1b, and CCL5 expression was assessed using qPCR and enzyme-linked immunosorbent assay.ResultsUsing an established mouse model of intrauterine inflammation, we demonstrate that the abrogation of TLR4 signaling eliminates the cytokine response in mother and fetus and prevents brain injury associated with increased expression of transcriptional effectors of the NOTCH signaling pathway, Hes1 and Hes5.ConclusionsThese data show that the activation of the TLR4 signaling pathway is necessary for the development of fetal brain injury in response to intrauterine inflammation.

Exposure to in utero inflammation increases locomotor activity, alters cognitive performance and drives vulnerability to cognitive performance deficits after acute immune activation

Fetal exposure to intrauterine inflammation (IUI) affects brain development. Using intrauterine lipopolysaccharide (LPS) administration to induce a localized, rather than a systemic, inflammation, we have previously shown that IUI increases cytokine expression and microglia number, and reduces white matter in the brains of exposed offspring. Clinical data suggest that IUI may increase the risk for cognitive and neurodevelopmental disorders, however, IUI is often found in the context of preterm birth, making it difficult to disentangle the adverse effects of inflammation from those related to prematurity. Therefore, using a mouse model of IUI that does not involve preterm birth, operant tasks were used to evaluate motivation, attention, impulsivity, and locomotion. IUI-exposed offspring were found to have increased locomotion and increased motivation (females only), and testing in the 5-choice serial reaction time task (5-CSRTT) showed that IUI-exposed offspring performed more trials and could respond accurately at a shorter stimulus length. We have previously shown that IUI animals have a potentiated cytokine response to a “second hit” (acute LPS injection) in adulthood, so animals’ performance in the 5CSRTT was evaluated following an acute injection of LPS. As opposed to the improved performance observed under baseline conditions, IUI exposed animals demonstrated a greater decrease in performance after an acute LPS administration. To identify putative molecular mechanisms underlying this potentiated decline in cognitive performance, PFC samples were collected immediately after post-LPS cognitive testing and targeted gene expression analysis was correlated with specific measures of cognitive performance. Three receptors important for neuron-microglia crosstalk were found to correlate with task performance in the males following acute LPS administration. These data demonstrate that early life exposure to localized inflammation of the uterus, in the absence of prematurity, increases locomotor activity and improves some aspects of cognitive performance, but drives a vulnerability for adult cognitive performance deficits in response to acute infection.

554: Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation-induced oxidative stress

Oxidative stress induces vasoconstriction, hypercoagulation and pathologic vascular remodeling. We hypothesized that maternally-administered melatonin may reduce oxidative stress, hypercoagulability and structural injury in placenta, and prevent fetal sequelae in a mouse model of intrauterine inflammation(IUI)-induced oxidative stress. CD1 pregnant dams were randomized to intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS) at E17 as follows: (1) control (C); (2) Melatonin (M); (3) LPS (L); (4) LPS with Melatonin group (LM). Doppler ultrasonography was utilized to obtain fetal and maternal hemodynamic measurements in utero. Proinflammatory mediators (NFkB, TNFα, and IL1β), oxidative stress markers (4-HNE) and antioxidant mediators (Nrf2, HO1) were analyzed in the placenta by real-time RT-qPCR and western blots. Confirmatory histochemistry (PTAH, H&E, Nissl staining) and immunohistochemical analyses (Vimentin & CD31, a vascular endothelial cell marker; and Iba1, a marker of microglial activation) were performed. The systolic/diastolic (S/D) ratio, resistance index (RI) and pulsatility index (PI) in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared to C, M, or ML groups. The rate of early diastolic notch in the UtA and the rate of absent end-diastolic flow (AEDF) in UA were significantly higher in L than C, M, or ML. Tei indices were significantly increased in L compared to C, M, or ML. The rate of abnormal Tei indices (>0.44) was significantly higher in L compared to C, M, or ML. The expression of SIRT1, Nrf2 and HO1 in the placenta were significantly decreased in L comparing to C or ML. The expression of NFkB, TNFα, and IL1β were significantly increased in L comparing to C, and ML. 4-HNE was increased in L comparing to C, M and ML. The area of vimentin in the placenta was decreased in L than C or M. PTAH staining in the placenta showed increased deposit of fibrin in L comparing to C, M, or ML. Iba1 expression was increased in fetal brains in L compared to C, M, and ML. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise and fetal neuroinflammation induced by intrauterine oxidative stress. Current results suggest that melatonin could serve as a new preventive and/or therapeutic agent to prevent fetal injury from IUI-induced oxidative stress.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Dynamic glucose enhanced MRI of the placenta in a mouse model of intrauterine inflammation

IntroductionWe investigated the feasibility of dynamic glucose enhanced (DGE) MRI in accessing placental function in a mouse model of intrauterine inflammatory injury (IUI). DGE uses the glucose chemical exchange saturation transfer (glucoCEST) effect to reflect infused d-glucose. MethodsIUI was induced in pregnant CD1 mice by intrauterine injection of lipopolysaccharide (LPS) on embryonic day 17. In vivo MRI was performed on an 11.7 T scanner at 6 h s after injury, and glucoCEST effect was measured using an on-resonance variable delay multi-pulse (onVDMP) technique. onVDMP acquisition was repeated over a period of 25 min, and d-glucose was infused 5 min after the start. The time-resolved glucoCEST signals were characterized using the normalized signal difference (ΔSN) between onVDMP-labeled and nonlabeled images. ResultsΔSN in the PBS-exposed placentae (n = 6) showed an initial drop between 1 and 3 min after infusion, followed by a positive peak between 5 and 20 min, the time period expected to be associated with the process of glucose uptake and transport. In the LPS-exposed placentae (n = 10), the positive peak was reduced or even absent, and the corresponding area-under-the-curve (AUC) was significantly lower than that in the controls. Particularly, the AUC maps suggested prominent group differences in the fetal side of the placenta. We also found that glucose transporter 1 in the LPS-exposed placentae did not respond to maternal glucose challenge. DiscussionDGE-MRI is useful for evaluating placental functions related to glucose utilization. The technique uses a non-toxic biodegradable agent (d-glucose) and thus has a potential for rapid translation to human studies of placental disorders.

P108: Supplementation of low dose fluoride during pregnancy alleviates perinatal brain injury of offspring in a mouse model of intrauterine inflammation

P108: Supplementation of low dose fluoride during pregnancy alleviates perinatal brain injury of offspring in a mouse model of intrauterine inflammation

Progesterone improves perinatal neuromotor outcomes in a mouse model of intrauterine inflammation via immunomodulation of the placenta

To assess the fetal neuroprotective potential of progesterone using a well-validated mouse model of lipopolysaccharide (LPS)-induced intrauterine inflammation (IUI). Embryonic day 17 pregnant mouse dams (n=69) were randomly allocated to receive 17-hydroxyprogesterone caproate (17-OHPC), micronized progesterone (MP), or vehicle 1hour prior to intrauterine injection of phosphate-buffered saline (PBS) or LPS. After 6hours, mice were killed for the collection of placentas and fetal brains, or pregnancy continued for the evaluation of preterm birth (PTB) and offspring neuromotor function. Placentas and fetal brains were analyzed by mini-mRNA array for 96 immune markers with individual confirmatory qPCR. Progesterone pre-treatment before LPS-induced IUI improved neuromotor tests in offspring at PND5 compared to no pre-treatment (P<.05). In placentas, 17-OHPC, but not MP, significantly reduced CXCL9 (P<.05) with a trend toward a lower level of CXCL10. In fetal brains, 17-OHPC significantly reduced CXCL9 compared to no pre-treatment (P<.05) and IL-1β compared to pre-treatment with MP (P<.01). Progesterone pre-treatment prior to LPS-induced IUI improved offspring neuromotor outcomes. 17-OHPC, but not MP, resulted in greater immunomodulation of T cell-mediated immunity in placenta and fetal brain, suggesting a possible mechanism for the observed neuroprotective effects.

597: Progesterone results in improved perinatal neurobehavioral outcomes in a mouse model of intrauterine inflammation via immunomodulation of placenta and fetal brain

597: Progesterone results in improved perinatal neurobehavioral outcomes in a mouse model of intrauterine inflammation via immunomodulation of placenta and fetal brain

Maternal CD8+ T-cell depletion alleviates intrauterine inflammation-induced perinatal brain injury.

We investigated the mechanisms by which CD8+ T-cell trafficking in placenta contributes to perinatal brain injury by studying effects of maternal CD8+ T-cell depletion (DEP) in a mouse model of intrauterine inflammation (IUI). Maternal CD8+ T cells were depleted with anti-CD8+ antibodies. IUI was induced with lipopolysaccharide (LPS). DEP was confirmed using flow cytometry. Preterm birth rate was evaluated. Offspring neurologic sequelae were assessed by Nissl staining, immune arrays, confirmatory individual TaqMan® gene assays, and neurobehavioral tests. DEP did not significantly prevent LPS-induced preterm birth but improved neurobehavioral performance (P<.001) and increased cortical neuronal density (P<.05) in LPS-exposed pups compared to controls. These changes were associated with decreased CCL3 and CXCL10 and increased CCL5 in DEP LPS-exposed mice. We demonstrate that DEP reduces perinatal brain injury following IUI. This supports a role for maternal CD8+ T-cell trafficking in placenta in mediating perinatal brain injury separate from preterm birth mechanisms.

Maternal Glucose Supplementation in a Murine Model of Chorioamnionitis Alleviates Dysregulation of Autophagy in Fetal Brain.

Fetal brain injury induced by intrauterine inflammation is a major risk factor for adverse neurological outcomes, including cerebral palsy, cognitive dysfunction, and behavioral disabilities. There are no adequate therapies for neuronal protection to reduce fetal brain injury, especially new strategies that may apply promptly and conveniently. In this study, we explored the effect of maternal glucose administration in a mouse model of intrauterine inflammation at term. Our results demonstrated that maternal glucose supplementation significantly increased survival birth rate and improved the neurobehavioral performance of pups exposed to intrauterine inflammation. Furthermore, we demonstrated that maternal glucose administration improved myelination and oligodendrocyte development in offspring exposed to intrauterine inflammation. Though the maternal blood glucose concentration was temporally prevented from decrease induced by intrauterine inflammation, the glucose concentration in fetal brain was not recovered by maternal glucose supplementation. The adenosine triphosphate (ATP) level and autophagy in fetal brain were regulated by maternal glucose supplementation, which may prevent dysregulation of cellular metabolism. Our study is the first to provide evidence for the role of maternal glucose supplementation in the cell survival of fetal brain during intrauterine inflammation and further support the possible medication with maternal glucose treatment.

In vivo assessment of the placental anatomy and perfusion in a mouse model of intrauterine inflammation.

Magnetic resonance imaging (MRI) provides useful markers to examine placental function. MRI features of placental injury due to intrauterine inflammation-a common risk during pregnancy, are not well known. To investigate the capability of structural MRI and intravoxel incoherent motion (IVIM) imaging in examining acute placental injury in a mouse model of intrauterine inflammation, as well as gestation-dependent placental changes. Prospective study. Pregnant CD1 mice were scanned on embryonic day 15 (E15, n = 40 placentas from six dams) and E17. On E17, mice were subjected to intrauterine injury by exposure to lipopolysaccharide (LPS, n = 25 placentas from three dams) or sham injury (n = 25 placentas from three dams). In vivo MRI was performed on an 11.7T Bruker scanner, using a fast spin-echo sequence and a diffusion-weighted echo-planar imaging (EPI) sequence. T2 -weighted MRI was acquired to evaluate placental volume. IVIM imaging was performed in a restricted field-of-view using 15 b-values from 10-800 s/mm2 , based on which, the pseudodiffusion fraction (f), pseudodiffusion coefficient (D*), and tissue water coefficient (D) were estimated with a two-step fitting procedure. Two-way analysis of variance (ANOVA) was used to evaluate the group differences. The placental volume increased by ∼21% from E15 to E17 (P < 0.01), and a 15% volume loss was observed at 6 hours after LPS exposure (P < 0.01). IVIM parameters (f, D*, and f·D*) were similar between the E15 and E17 sham groups (P > 0.05), which was significantly reduced in the LPS-exposed placentas compared to the shams (P < 0.001). D values decreased from E15 to E17 (P < 0.05), which were further reduced after LPS exposure (P < 0.05). Changes in placental area and vascular density were histologically identified in the LPS-exposed group, along with gestation-dependent changes. Our results suggested structural MRI and IVIM measurements are potential markers for detecting acute placental injury after intrauterine inflammation. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1260-1267.

Functional changes in hippocampal synaptic signaling in offspring survivors of a mouse model of intrauterine inflammation

BackgroundRecent evidence suggests that exposure to intrauterine inflammation causes acute fetal brain injury and is linked to a spectrum of neurobehavioral disorders. In a rodent model of intrauterine inflammation induced by lipopolysaccharide (LPS) exposure in utero, activated microglia can be detected in the hippocampus of offspring survivors, as late as 60 days postnatal (DPN). Given that the hippocampus is important for learning and memory, these results suggest that in utero inflammation underlies long-term cognitive deficits observed in children/survivors.MethodsAn established mouse model of LPS-induced intrauterine inflammation was used to study hippocampal function from offspring at 44–59 DPN. Microgliosis was examined at 45 DPN. Extracellular field recordings of synaptic transmission were performed on acute hippocampal slices.ResultsLPS offspring mice displayed persistent microglial activation and increased CA3–CA1 excitatory synaptic strength, which can be explained in part by an increase in the probability of glutamate release, and reduced long-term synaptic potentiation compared to control mice.ConclusionsThese results offer a mechanistic explanation for the cognitive and behavioral deficits observed in survivors of preterm birth caused by intrauterine inflammation.

P2X7 receptor blockade prevents preterm birth and perinatal brain injury in a mouse model of intrauterine inflammation.

The P2X7 is an adenosine triphosphate (ATP)-gated ion channel involved in several facets of immune activation and neuronal function through its importance in interleukin (IL)-1β secretion. We hypothesized that blockade of P2X7 would prevent perinatal brain injury associated with exposure to intrauterine (IU) inflammation. Dams received 45 mg/kg of Brilliant Blue G (BBG), a specific P2X7 receptor (P2X7R) antagonist, on gestation day 17 (E17) prior to administration of lipopolysaccharide (LPS) or phosphate-buffered saline (PBS). Furthermore, we utilized embryo transfer experiments to delineate whether the P2X7 was the key mediator of IU inflammation-associated brain injury on maternal or fetal sides. In these experiments, P2X7-/- dams were embryo-transferred wild type embryos and wild type dams were embryo-transferred P2X7-/- embryos. In the mouse model of intrauterine inflammation, pharmacologic blockade of P2X7R reduced preterm birth rate, improved offspring performance on neuromotor tests as well as the dendritic arborization and density of cortical neurons. Embryo transfer experiments demonstrated the importance of maternal P2X7R in IU inflammation-mediated effects on offspring. Both genetic and pharmacologic blockade of IL-1β signaling, by targeting maternal P2X7R, ameliorated perinatal brain injury following exposure to IU inflammation. Specific targeting of maternal P2X7R may provide a clinically useful tool to prevent both preterm birth and prematurity-associated perinatal brain injury, and further studies are urgently needed.

Maternal dendrimer-based therapy for inflammation-induced preterm birth and perinatal brain injury

Preterm birth is a major risk factor for adverse neurological outcomes in ex-preterm children, including motor, cognitive, and behavioral disabilities. N-acetyl-L-cysteine therapy has been used in clinical studies; however, it requires doses that cause significant side effects. In this study, we explore the effect of low dose N-acetyl-L-cysteine therapy, delivered using a targeted, systemic, maternal, dendrimer nanoparticle (DNAC), in a mouse model of intrauterine inflammation. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the preterm birth rate and altered placental immune profile with decreased CD8+ T-cell infiltration. Furthermore, we demonstrated that DNAC improved neurobehavioral outcomes and reduced fetal neuroinflammation and long-term microglial activation in offspring. Our study is the first to provide evidence for the role of CD8+ T-cell in the maternal-fetal interface during inflammation and further support the efficacy of DNAC in preventing preterm birth and prematurity-related outcomes.

293: Receptor for advanced glycation end-products (RAGE) expression impacts neonatal and infant mortality and neurodevelopmental outcome in a mouse model of intra-uterine inflammation

293: Receptor for advanced glycation end-products (RAGE) expression impacts neonatal and infant mortality and neurodevelopmental outcome in a mouse model of intra-uterine inflammation

Murine model: maternal administration of stem cells for prevention of prematurity

Using a mouse model of intrauterine inflammation, we have demonstrated that exposure to inflammation induces preterm birth and perinatal brain injury. Mesenchymal stem cells (MSCs) have been shown to exhibit immunomodulatory effects in many inflammatory conditions. We hypothesized that treatment with human adipose tissue-derived MSCs may decrease the rate of preterm birth and perinatal brain injury through changes in antiinflammatory and regulatory milieu. A mouse model of intrauterine inflammation was used with the following groups: (1) control; (2) intrauterine inflammation (lipopolysaccharide); and (3) intrauterine lipopolysaccharide+intraperitoneal (MSCs). Preterm birth was investigated. Luminex multiplex enzyme-linked immunosorbent assays were performed for protein levels of cytokines in maternal and fetal compartments. Immunofluorescent staining was used to identify and localize MSCs and to examine microglial morphologic condition and neurotoxicity in perinatal brain. Behavioral testing was performed at postnatal day 5. Pretreatment with MSCs significantly decreased the rate of preterm birth by 21% compared with the lipopolysaccharide group (P<.01). Pretreatment was associated with increased interleukin-10 in maternal serum, increased interleukin-4 in placenta, decreased interleukin-6 in fetal brain (P<.05), decreased microglial activation (P<.05), and decreased fetal neurotoxicity (P<.05). These findings were associated with improved neurobehavioral testing at postnatal day 5 (P<.05). Injected MSCs were localized to placenta. Maternally administered MSCs appear to modulate maternal and fetal immune response to intrauterine inflammation in the model and decrease preterm birth, perinatal brain injury, and motor deficits in offspring mice.

Fetal uptake of intra-amniotically delivered dendrimers in a mouse model of intrauterine inflammation and preterm birth

Intrauterine inflammation is associated with preterm birth and can lead to fetal neuroinflammation and neurobehavioral disorders in newborns. Dendrimers can intrinsically target and deliver drugs for the treatment of neuroinflammation. We explore whether hydroxyl polyamidoamine (PAMAM) dendrimer (G4-OH)-based nanomedicines can be delivered to the fetus by intra-amniotic administration, in a mouse model of intrauterine inflammation. The time-dependent accumulation of G4-OH-fluorophore conjugate was quantified by fluorescence. These studies suggest that, after intra-amniotic administration, there is significant accumulation of dendrimer in the fetus gut and brain. In addition, there is some fetal–maternal transport of the dendrimer. Confocal microscopy confirmed the presence of G4-OH in the fetal brain, with a large accumulation in the brain blood vessels and the brain parenchyma, and some microglial uptake. We believe that intra-amniotic administration of G4-OH-drug nanomedicines may enable the treatment of diseases related to intrauterine inflammation and fetal neuroinflammation. From the Clinical EditorUsing a mouse model of intrauterin inflammation leading to neuroinflammation in the fetus, these investigators demonstrate that intra-amniotic delivery of hydroxyl polyamidoamine (PAMAM) dendrimer (G4-OH)-based nanomedicines may provide an effective method in preventing this complication.