Dataset Information

Healing of Preterm Ruptured Fetal Membranes.

ABSTRACT: Preterm premature rupture of membrane (pPROM) is associated with 30-40% of preterm births. Infection is considered a leading cause of pPROM due to increased levels of proinflammatory cytokines in amniotic fluid. Only 30%, however, are positive for microbial organisms by amniotic fluid culture. Interestingly, in some pregnancies complicated by preterm premature rupture of membranes (pPROM), membranes heal spontaneously and pregnancy continues until term. Here, we investigated mechanisms of amnion healing. Using a preclinical mouse model, we found that small ruptures of the fetal membrane closed within 72?h whereas healing of large ruptures was only 40%. Small rupture induced transient upregulation of cytokines whereas large ruptures elicited sustained upregulation of proinflammatory cytokines in the fetal membranes. Fetal macrophages from amniotic fluid were recruited to the wounded amnion where macrophage adhesion molecules were highly expressed. Recruited macrophages released limited and well-localized amounts of IL-1? and TNF which facilitated epithelial-mesenchymal transition (EMT) and epithelial cell migration. Arg1?+?macrophages dominated within 24?h. Migration and healing of the amnion mesenchymal compartment, however, remained compromised. These findings provide novel insights regarding unique healing mechanisms of amnion.

SUBMITTER: Mogami H

PROVIDER: S-EPMC5640674 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Healing of Preterm Ruptured Fetal Membranes.

Mogami Haruta H Hari Kishore Annavarapu A Akgul Yucel Y Word R Ann RA

Scientific reports 20171013 1

Preterm premature rupture of membrane (pPROM) is associated with 30-40% of preterm births. Infection is considered a leading cause of pPROM due to increased levels of proinflammatory cytokines in amniotic fluid. Only 30%, however, are positive for microbial organisms by amniotic fluid culture. Interestingly, in some pregnancies complicated by preterm premature rupture of membranes (pPROM), membranes heal spontaneously and pregnancy continues until term. Here, we investigated mechanisms of amnion ...[more]

PMID: 29030612

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Project description:BackgroundGlobally, preterm birth remains the leading cause of death in children younger than 5 years old. Spontaneous preterm birth is comprised of two events that may or may not occur simultaneously: preterm labor and preterm prelabor rupture of membranes (PPROM). To further explore the concept that spontaneous preterm birth can result from the initializing of two separate but overlapping pathological events, we compared fetal membrane tissue from preterm labor deliveries to fetal tissue from preterm labor with PPROM deliveries. We hypothesized that the fetal membrane tissue from preterm labor with PPROM cases will have an RNA-seq profile divergent from the fetal membrane tissue from preterm labor controls.MethodsChorioamnion, separated into amnion and chorion, was collected from eight gestationally age-matched cases and controls within 15 min of birth, and analyzed using RNA sequencing. Pathway enrichment analyses and functional annotations of differentially expressed genes were performed using KEGG and Gene Ontogeny Pathway enrichment analyses.ResultsA total of 1466 genes were differentially expressed in the amnion, and 484 genes were differentially expressed in the chorion (log2 fold change > 1, FDR < 0.05) in cases (preterm labor with PPROM), versus controls (preterm labor only). In the amnion, the most significantly enriched (FDR < 0.01) KEGG pathway among down-regulated genes was the extracellular matrix receptor interaction pathway. Seven of the most significantly enriched pathways were comprised of multiple genes from the COL family, including COL1A, COL3A1, COL4A4, and COL4A6. In the chorion, the most significantly enriched KEGG pathways in up-regulated genes were chemokine, NOD receptor, Toll-like receptor, and cytokine-cytokine receptor signaling pathways. Similarly, KEGG pathway enrichment analysis for up-regulated genes in the amnion included three inflammatory pathways: cytokine-cytokine interaction, TNF signaling and the CXCL family. Six genes were significantly up regulated in chorionic tissue discriminated between cases (preterm labor with PPROM) and controls (preterm labor only) including GBP5, CXCL9, ALPL, S100A8, CASP5 and MMP25.ConclusionsIn our study, transcriptome analysis of preterm fetal membranes revealed distinct differentially expressed genes for PPROM, separate from preterm labor. This study is the first to report transcriptome data that reflects the individual pathophysiology of amnion and chorion tissue from PPROM deliveries.

Project description:BACKGROUND:Preterm birth (PTB), defined as infant delivery before 37 weeks of completed gestation, results from the interaction of both genetic and environmental components and constitutes a complex multifactorial syndrome. Transcriptome analysis of PTB has proven challenging because of the multiple causes of PTB and the numerous maternal and fetal gestational tissues that must interact to facilitate parturition. The transcriptome of the chorioamnion membranes at the site of rupture in PTB and term fetuses may reflect the molecular pathways of preterm labor. METHODS:In this work, chorioamnion membranes from severe preterm and term fetuses were analyzed using RNA sequencing. Functional annotations and pathway analysis of differentially expressed genes were performed with the GAGE and GOSeq packages. A subset of differentially expressed genes in PTB was validated in a larger cohort using qRT-PCR and by comparing our results with genes and pathways previously reported in the literature. RESULTS:A total of 270 genes were differentially expressed (DE): 252 were upregulated and 18 were down-regulated in severe preterm births relative to term births. Inflammatory and immunological pathways were upregulated in PTB. Both types of pathways were previously suggested to lead to PTB. Pathways that were not previously reported in PTB, such as the hemopoietic pathway, appeared upregulated in preterm membranes. A group of 18 downregulated genes discriminated between term and severe preterm cases. These genes potentially characterize a severe preterm transcriptome pattern and therefore are candidate genes for understanding the syndrome. Some of the downregulated genes are involved in the nervous system, morphogenesis (WNT1, DLX5, PAPPA2) and ion channel complexes (KCNJ16, KCNB1), making them good candidates as biomarkers of PTB. CONCLUSIONS:The identification of this DE gene pattern will help with the development of a multi-gene disease classifier. These markers were generated in an admixed South American population in which PTB has a high incidence. Since the genetic background may differentially impact different populations, it is necessary to include populations such as those from South America and Africa, which are usually excluded from high-throughput approaches. These classifiers should be compared to those in other populations to obtain a global landscape of PTB.

Dataset Information

Healing of Preterm Ruptured Fetal Membranes.

Publications

Healing of Preterm Ruptured Fetal Membranes.

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