Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Large-scale downregulation of cytokeratins in amniotic epithelium after Group B Streptococcus choriodecidual infection in Macaca nemestrina: a pathway to PPROM

ABSTRACT: Early events leading to intrauterine infection remain poorly defined, but may hold the key to a therapeutic intervention for preterm delivery. To determine early molecular pathways associated with membrane weakening that may progress to preterm premature rupture of membranes (PPROM), we examined the effects of Group B Streptococcus (GBS) on fetal membranes after a choriodecidual infection. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received choriodecidual inoculation of either: 1) Group B Streptococcus (n=5) or 2) saline (n=5). Cesarean section and fetal necropsy was performed in the first week after GBS or saline inoculation regardless of labor. Macaca nemestrina chorioamnion samples were obtained at the site of inocculation immediately after cesarean delivery 4 days after GBS inoculation and 7 days after saline inoculation. RNA was extracted and profiled by microarray. Results were analyzed using single gene, Gene Set, and Ingenuity Pathway Analysis. Validation was by RT-PCR and immunohistochemistry.

ORGANISM(S): Macaca nemestrina

SUBMITTER: Richard Beyer

PROVIDER: E-GEOD-46290 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Group B streptococcal infection of the choriodecidua induces dysfunction of the cytokeratin network in amniotic epithelium: a pathway to membrane weakening.

Vanderhoeven Jeroen P JP Bierle Craig J CJ Kapur Raj P RP McAdams Ryan M RM Beyer Richard P RP Bammler Theo K TK Farin Federico M FM Bansal Aasthaa A Spencer Min M Deng Mei M Gravett Michael G MG Rubens Craig E CE Rajagopal Lakshmi L Adams Waldorf Kristina M KM

PLoS pathogens 20140306 3

Early events leading to intrauterine infection remain poorly defined, but may hold the key to preventing preterm delivery. To determine molecular pathways within fetal membranes (chorioamnion) associated with early choriodecidual infection that may progress to preterm premature rupture of membranes (PPROM), we examined the effects of a Group B Streptococcus (GBS) choriodecidual infection on chorioamnion in a nonhuman primate model. Ten chronically catheterized pregnant monkeys (Macaca nemestrina ...[more]

PMID: 24603861

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Project description:Mechanisms underlying in utero fetal lung injury remain poorly defined, and a greater understanding of pathways regulating these processes may lead to novel therapies that prevent lung injury before birth. MicroRNAs (miRNAs) are small non-coding, endogenous RNAs that regulate gene expression and have been implicated in the pathogenesis of lung disease. We sought to determine whether differentially expressed miRNAs in the fetal lung following choriodecidual infection are associated with elevation of amniotic fluid (AF) cytokine levels and acute lung injury in a nonhuman primate model. After inoculating ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) with either Group B Streptococcus (GBS) 1 x 106 colony forming units (n=5) or saline (n=5) in the choriodecidual space, we extracted fetal lung mRNA and miRNA and profiled changes in expression. We identified 9 differentially expressed miRNAs (p<0.05, >1.5 fold change) in the GBS-exposed fetal lungs by microarray, but of these only miR-155-5p was significantly elevated by qRT-PCR (p=0.016). The microarray log2 intensity of miR-155-5p positively correlated with fetal lung injury scores and AF IL-1? and TNF-??levels (R2=0.54, p=0.016). In situ hybridization revealed that miR-155-5p is expressed throughout the fetal lung, which led us to investigate mechanisms that regulate miR-155-5p expression. Significantly elevated miR-155-5p expression was observed when immortalized human fetal airway epithelial (FeAE) cells were exposed to IL-6 and TNF-??. Overexpression of miR-155-5p in FeAE cells increased production of IL-6, CCL5/RANTES and CXCL10/IP-10. Using a luciferase reporter assay, we validated FGF9 as an authentic target of miR-155-5p, which is essential to development of the lung mesenchyme and distal epithelial branching. Collectively, these results suggest that a choriodecidual inflammatory response leads to increased AF cytokine levels, which induce miR-155-5p expression. In turn, miR-155-5p activates and recruits leukocytes (IL-6, CCL5/RANTES) and inhibits fetal lung angiogenesis (CXCL10/IP-10), meschenchymal development and epithelial branching (targets FGF9 mRNA). A therapy to antagonize miR-155-5p may ameliorate perinatal lung injury. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received choriodecidual inoculation of either: 1) Group B Streptococcus (n=5) or 2) saline (n=5). Cesarean section and fetal necropsy was performed in the first week after GBS or saline inoculation regardless of labor. RNA was extracted from fetal lungs and profiled by microarray. Results were analyzed using single gene, Gene Set, and Ingenuity Pathway Analysis. Validation was by RT-PCR and immunohistochemistry.

Dataset Information

Large-scale downregulation of cytokeratins in amniotic epithelium after Group B Streptococcus choriodecidual infection in Macaca nemestrina: a pathway to PPROM

Publications

Group B streptococcal infection of the choriodecidua induces dysfunction of the cytokeratin network in amniotic epithelium: a pathway to membrane weakening.

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