Intra-amniotic Balloon Inflation Induces an Inflammatory “Pulse” and Labor in Nonhuman Primates
Ontology highlight
ABSTRACT:
ORGANISM(S): Macaca nemestrina Macaca mulatta
PROVIDER: GSE63274 | GEO | 2015/09/11
SECONDARY ACCESSION(S): PRJNA267264
REPOSITORIES: GEO
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Project description:Uterine stretch is thought to induce preterm labor in women with twin and higher order pregnancies, but the pathophysiology remains unclear. We investigated the pathogenesis of stretch-induced preterm birth for the first time in a pregnant nonhuman primate model. Eleven chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received either: 1) inflation of intra-amniotic balloons (N=6) or 2) saline inoculation (N=5). Cesarean section and fetal necropsy was performed due to preterm labor or to collect tissues, except in one case where the animal delivered spontaneously, reducing samples for microarray analysis to ten (five stretch and five control animals). Amniotic fluid and maternal plasma were analyzed for multiple cytokines and prostaglandins using Luminex, enzyme-linked immunosorbent assay and Analysis of Covariance. Ribonucleic acid was extracted from the myometrium in the lower uterus at Cesarean section and analyzed by microarray and quantitative reverse transcriptase polymerase chain reaction.
2015-09-11 | E-GEOD-63274 | biostudies-arrayexpress
Project description:Preterm birth is a leading cause of neonatal morbidity and mortality. Microbial infection and inflammation of the amniotic cavity are associated with the majority of early preterm births and thought to arise from ascension of bacteria from the lower genital tract. Group B Streptococci (GBS) are beta-hemolytic, gram-positive bacteria, which commonly colonize the vagina and have been recovered from the amniotic fluid in cases of preterm birth. Host immune defenses that are critical for prevention of microbial invasion of the amniotic cavity (MIAC) and preterm labor are not completely understood. We recently showed that increased expression of the hemolytic pigment promotes GBS penetration of human placenta ex vivo and hyperhemolytic/hyperpigmented GBS strains with mutations in the hemolysin repressor (CovR/CovS) can be isolated from women in preterm labor. To understand placental/ choriodecidual immune responses that are necessary to prevent MIAC and preterm labor, we utilized a unique chronically catheterized nonhuman primate model that closely emulates human pregnancy. We observed that preterm labor, MIAC, and fetal injury occurred significantly more frequently in pregnant nonhuman primates infected with hyperpigmented GBS (ΔcovR) despite the strong induction of proinflammatory responses in the chorioamnion. Placental histopathology revealed a systematic progression in development of chorioamnionitis in GBSΔcovR animals beginning with chorionic vasculitis and subsequently progressing to neutrophilic infiltration in the chorioamnion.
2016-04-26 | GSE80248 | GEO
Project description:Preterm birth is multifactorial in origin with several distinct clinical phenotypes of differing etiologies, including idiopathic preterm birth. Preterm birth involves the interaction of genetic, societal and environmental factors such as nutrition, lifestyle and stress that may modulate the length of gestation via the epigenome. DNA methylation is a well-studied epigenetic modification whereby promoter methylation commonly represses gene expression and vice versa. Myometrial tissue was obtained at cesarean section at term with or without labor, preterm without labor, idiopathic preterm labor, and twin gestations with labor. Differences in the myometrial epigenomes were identified at gene promoters, CpG islands, CpG island shores and shelves, gene bodies across the genome between the groups of women with preterm labor of different phenotypes vs. normal term labor. Functional clustering analysis indicated the significantly enriched pathways of hypomethylated genes (permissive) were related to acute inflammatory and acute-phase responses. By contrast, genes that are hypermethylated (repressive) revealed enrichment for contractile fibers and cell. This study provides the first high-resolution DNA methylome of human myometrium with evidence for differences in the methylome that may relate to idiopathic preterm birth via regulation of gene expression. The findings extend previous observations that idiopathic preterm labor is associated with subclinical intrauterine infection and inflammatory pathways and point to targets for further molecular characterization of preterm delivery. Comparison of the human myometrial epigenomes in pregnancies with preterm labor of different phenotypes vs. normal term labor
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Project description:Preterm birth is multifactorial in origin with several distinct clinical phenotypes of differing etiologies, including idiopathic preterm birth. Preterm birth involves the interaction of genetic, societal and environmental factors such as nutrition, lifestyle and stress that may modulate the length of gestation via the epigenome. DNA methylation is a well-studied epigenetic modification whereby promoter methylation commonly represses gene expression and vice versa. Myometrial tissue was obtained at cesarean section at term with or without labor, preterm without labor, idiopathic preterm labor, and twin gestations with labor. Differences in the myometrial epigenomes were identified at gene promoters, CpG islands, CpG island shores and shelves, gene bodies across the genome between the groups of women with preterm labor of different phenotypes vs. normal term labor. Functional clustering analysis indicated the significantly enriched pathways of hypomethylated genes (permissive) were related to acute inflammatory and acute-phase responses. By contrast, genes that are hypermethylated (repressive) revealed enrichment for contractile fibers and cell. This study provides the first high-resolution DNA methylome of human myometrium with evidence for differences in the methylome that may relate to idiopathic preterm birth via regulation of gene expression. The findings extend previous observations that idiopathic preterm labor is associated with subclinical intrauterine infection and inflammatory pathways and point to targets for further molecular characterization of preterm delivery.
2017-05-04 | GSE71123 | GEO
Project description:The amniotic fluid (AF) cell-free (cf) RNA was shown to reflect physiological and pathological processes in pregnancy, but its value in prediction of spontaneous preterm delivery is unknown. Here we profiled cfRNA in AF samples collected from women who underwent transabdominal amniocentesis after an episode of spontaneous preterm labor and subsequently delivered within 24h (n=10) or later (n=28) in gestation. Expression of known placental single cell (sc) RNA-Seq signatures were quantified in AF cfRNA and compared between groups. Random forest models were applied to predict time to delivery after amniocentesis. There were 2385 genes differentially expressed in AF samples of women who delivered within 24 hours of amniocentesis compared to gestational age-matched samples from women who delivered after 24 hours of amniocentesis.Genes with cfRNA changes were associated with immune and inflammatory processes related to the onset of labor, and expression of placental scRNA-Seq signatures of immune cells were increased with imminent delivery. AF transcriptomic prediction models captured these effects and predicted delivery within 24 hours of amniocentesis (AUROC =0.81). These results may inform development of biomarkers for spontaneous preterm birth.
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Project description:<p>Nonalcoholic steatohepatitis (NASH) prevalence is rising with no pharmacotherapy approved. A major hurdle in NASH drug development is the poor translatability of preclinical studies to safe/effective clinical outcomes, and recent failures highlight a need to identify new targetable pathways. Dysregulated glycine metabolism has emerged as a causative factor and therapeutic target in NASH. Here, we report that the tripeptide DT-109 (Gly-Gly-Leu) dose-dependently attenuates steatohepatitis and fibrosis in mice. To enhance the probability of successful translation, we developed a nonhuman primate model that histologically and transcriptionally mimics human NASH. Applying a multiomics approach combining transcriptomics, proteomics, metabolomics and metagenomics, we found that DT-109 reverses hepatic steatosis and prevents fibrosis progression in nonhuman primates, not only by stimulating fatty acid degradation and glutathione formation, as found in mice, but also by modulating microbial bile acid metabolism. Our studies describe a highly translatable NASH model and highlight the need for clinical evaluation of DT-109.</p>
2023-04-13 | MTBLS5005 | MetaboLights
Project description:Preterm birth is often predisposed by chorioamnionitis (CA) and CA affects the fetal gut and lungs via intra-amniotic (IA) inflammation, thus accentuating the proinflammatory effects of preterm birth. It is not known if IA inflammation also affects other perfusion-sensitive organs (e.g., kidneys) before and after preterm birth. Using preterm pigs as model for preterm infants, we hypothesized that CA induces fetal and neonatal renal dysfunctions that can intially be detected via plasma proteome, partly explaining the frequent renal dysfunction in preterm infants. Fetal pigs (88% gestation) were given an IA dose of lipopolysaccharide (LPS, 1 mg/kg, n=28), delivered preterm by cesarean section three days later, and compared with controls (CON, n=26) at birth and postnatal day five. Plasma proteome and protein markers of inflammatory pathways were evaluated.
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