Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature.
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ABSTRACT: Objective
The purpose of this study was to identify which biological processes may be involved in normal labor.Study design
Transcriptional profiles for chorioamniotic membranes (n = 24) and blood (n = 20) were generated from patients at term with no labor (TNL) and in labor (TIL).Results
Expression of 197 transcripts (P < or = .02) differentiated TIL and TNL chorioamniotic membrane samples. Gene Ontology analysis indicated that TIL samples had increased expression of multiple chemokines and transcripts associated with neutrophil and monocyte recruitment. Microarray results were verified using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) with independent samples. Transcriptional profiles from blood RNA revealed no Gene Ontology category enrichment of discriminant probe sets.Conclusion
Labor induces gene expression changes consistent with localized inflammation, despite the absence of histologically detectable inflammation.
SUBMITTER: Haddad R
PROVIDER: S-EPMC1800883 | biostudies-literature | 2006 Aug
REPOSITORIES: biostudies-literature
Publications
Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature.
Haddad Ramsi R Tromp Gerard G Kuivaniemi Helena H Chaiworapongsa Tinnakorn T Kim Yeon Mee YM Mazor Moshe M Romero Roberto R
American journal of obstetrics and gynecology 20060801 2
<h4>Objective</h4>The purpose of this study was to identify which biological processes may be involved in normal labor.<h4>Study design</h4>Transcriptional profiles for chorioamniotic membranes (n = 24) and blood (n = 20) were generated from patients at term with no labor (TNL) and in labor (TIL).<h4>Results</h4>Expression of 197 transcripts (P < or = .02) differentiated TIL and TNL chorioamniotic membrane samples. Gene Ontology analysis indicated that TIL samples had increased expression of mul ...[more]
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Project description:Inflammasomes are cytosolic multiprotein complexes that orchestrate inflammation in response to pathogens and endogenous danger signals. Herein, we determined whether the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis (1) express major inflammasome components; (2) express caspase (CASP)-1 and CASP-4 as well as their active forms; (3) exhibit apoptosis-associated speck-like protein containing a CARD (ASC)/CASP-1 complex formation; and (4) release the mature forms of interleukin (IL)-1? and IL-18. We utilized quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, immunoblotting, and immunohistochemistry to determine the messenger RNA (mRNA) and protein expression of major inflammasome components, nucleotide-binding oligomerization domain (NOD) proteins, and the pro- and mature/active forms of CASP-1, CASP-4, IL-1?, and IL-18. The ASC/CASP-1 complex formation was determined using an in situ proximity ligation assay. When comparing the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis to those without this placental lesion, we found that (1) the mRNA of NLR family pyrin domain-containing protein ( NLRP) 1, NLRP3, NLR family CARD domain-containing protein 4 ( NLRC4), and NOD2 were higher; (2) the NLRP3 protein was increased; (3) the mRNA and active form (p10) of CASP-1 were greater; (4) the mRNA and active form of CASP-4 were increased; (5) the mRNA and mature form of IL-1? were higher; (6) the mature form of IL-18 was elevated; and (7) ASC/CASP-1 complex formation was increased. In conclusion, spontaneous preterm labor with acute histologic chorioamnionitis is characterized by an upregulation of NLRP3 and the active form of CASP-4, as well as increased ASC/CASP-1 complex formation, which may participate in the activation of CASP-1 and the maturation of IL-1? and IL-18 in the chorioamniotic membranes. These findings provide the first evidence that supports a role for the inflammasome in the pathological inflammation implicated in spontaneous preterm labor with acute histologic chorioamnionitis.
| S-EPMC5933090 | biostudies-literature
Project description:Inflammasomes are cytosolic signaling platforms that regulate the activation of caspase (CASP)-1, which induces the maturation of interleukin (IL)-1β and IL-18. Herein, we determined whether the chorioamniotic membranes from women in spontaneous labor at term with acute histologic chorioamnionitis express major inflammasome components and whether these changes are associated with the activation of CASP-1 and CASP-4 and the release of mature IL-1β and IL-18. When comparing the chorioamniotic membranes from women in spontaneous labor at term with acute histologic chorioamnionitis to those without this placental lesion, we found that (1) the messenger RNA (mRNA) abundance of NLR family pyrin domain containing 3 ( NLRP3), NLR family CARD domain containing 4 ( NLRC4), absent in melanoma 2 ( AIM2), and nucleotide binding oligomerization domain 2 ( NOD2) was higher; (2) the NLRP3 and NLRC4 protein quantities were increased; (3) the mRNA and protein expressions of CASP-1 and its active forms were greater; (4) CASP-4 was increased at the mRNA level only; (5) the mRNA and protein expressions of IL-1β and its mature form were higher; and (6) a modest increase in the total protein concentration and abundance of the mature form of IL-18 was observed. In vitro incubation of the chorioamniotic membranes with the CASP-1 inhibitor, VX765, decreased the release of endotoxin-induced IL-1β and IL-18 (2-fold) but not IL-6 or tumor necrosis factor α. In conclusion, spontaneous labor at term with acute histologic chorioamnionitis is characterized by an upregulation of inflammasome components which, in turn, may participate in the activation of CASP-1 and lead to the release of mature IL-1β by the chorioamniotic membranes. These results support a role for the inflammasome in the mechanisms responsible for spontaneous labor at term with acute histologic chorioamnionitis.
| S-EPMC5933099 | biostudies-literature
Project description:BackgroundDecidual senescence has been considered a mechanism of disease for spontaneous preterm labor in the absence of severe acute inflammation. Yet, signs of cellular senescence have also been observed in the chorioamniotic membranes from women who underwent the physiological process of labor at term.ObjectiveWe aimed to investigate whether, in the absence of acute histologic chorioamnionitis, the chorioamniotic membranes from women who underwent spontaneous preterm labor or labor at term exhibit signs of cellular senescence.Study designChorioamniotic membrane samples were collected from women who underwent spontaneous preterm labor or labor at term. Gestational age-matched nonlabor controls were also included. Senescence-associated genes/proteins were determined using reverse transcription quantitative polymerase chain reaction analysis (n = 7-9 each for array; n = 26-28 each for validation), enzyme-linked immunosorbent assays (n = 7-9 each), immunoblotting (n = 6-7 each), and immunohistochemistry (n = 7-8 each). Senescence-associated β-galactosidase activity (n = 7-11 each) and telomere length (n = 15-22 each) were also evaluated.ResultsIn the chorioamniotic membranes without acute histologic chorioamnionitis: (1) the expression profile of senescence-associated genes was different between the labor groups (term in labor and preterm in labor) and the nonlabor groups (term no labor and preterm no labor), yet there were differences between the term in labor and preterm in labor groups; (2) most of the differentially expressed genes among the groups were closely related to the tumor suppressor protein (TP53) pathway; (3) the expression of TP53 was down-regulated in the term in labor and preterm in labor groups compared to their nonlabor counterparts; (4) the expression of CDKN1A (gene coding for p21) was up-regulated in the term in labor and preterm in labor groups compared to their nonlabor counterparts; (5) the expression of the cyclin kinase CDK2 and cyclins CCNA2, CCNB1, and CCNE1 was down-regulated in the preterm in labor group compared to the preterm no labor group; (6) the concentration of TP53 was lower in the preterm in labor group than in the preterm no labor and term in labor groups; (7) the senescence-associated β-galactosidase activity was greater in the preterm in labor group than in the preterm no labor and term in labor groups; (8) the concentration of phospho-S6 ribosomal protein was reduced in the term in labor group compared to its nonlabor counterpart, but no differences were observed between the preterm in labor and preterm no labor groups; and (9) no significant differences were observed in relative telomere length among the study groups (term no labor, term in labor, preterm no labor, and preterm in labor).ConclusionIn the absence of acute histologic chorioamnionitis, signs of cellular senescence are present in the chorioamniotic membranes from women who underwent spontaneous preterm labor compared to those who delivered preterm in the absence of labor. However, the chorioamniotic membranes from women who underwent spontaneous labor at term did not show consistent signs of cellular senescence in the absence of histologic chorioamnionitis. These results suggest that different pathways are implicated in the pathological and physiological processes of labor.
| S-EPMC5800423 | biostudies-literature
Project description:The link between histologic acute chorioamnionitis and infection is well established in preterm deliveries, but less well-studied in term pregnancies, where infection is much less common.We conducted a secondary analysis among 195 low-risk women with term pregnancies enrolled in a randomized trial. Histologic and microbiologic evaluation of placentas included anaerobic and aerobic cultures (including mycoplasma/ureaplasma species) as well as PCR. Infection was defined as ≥1,000 cfu of a single known pathogen or a ≥2 log difference in counts for a known pathogen versus other organisms in a mixed culture. Placental membranes were scored and categorized as: no chorioamnionitis, Grade 1 (subchorionitis and patchy acute chorioamnionitis), or Grade 2 (severe, confluent chorioamnionitis). Grade 1 or grade 2 histologic chorioamnionitis was present in 34% of placentas (67/195), but infection was present in only 4% (8/195). Histologic chorioamnionitis was strongly associated with intrapartum fever >38°C [69% (25/36) fever, 26% (42/159) afebrile, P<.0001]. Fever occurred in 18% (n = 36) of women. Most febrile women [92% (33/36)] had received epidural for pain relief, though the association with fever was present with and without epidural. The association remained significant in a logistic regression controlling for potential confounders (OR = 5.8, 95% CI = 2.2,15.0). Histologic chorioamnionitis was also associated with elevated serum levels of interleukin-8 (median = 1.3 pg/mL no histologic chorioamnionitis, 1.5 pg/mL Grade 1, 2.1 pg/mL Grade 2, P = 0.05) and interleukin-6 (median levels = 2.2 pg/mL no chorioamnionitis, 5.3 pg/mL Grade 1, 24.5 pg/mL Grade 2, P = 0.02) at admission for delivery as well as higher admission WBC counts (mean = 12,000 cells/mm(3) no chorioamnionitis, 13,400 cells/mm(3) Grade 1, 15,700 cells/mm(3) Grade 2, P = 0.0005).Our results suggest histologic chorioamnionitis at term most often results from a noninfectious inflammatory process. It was strongly associated with fever, most of which was related to epidural used for pain relief. A more 'activated' maternal immune system at admission was also associated with histologic chorioamnionitis.
| S-EPMC3296706 | biostudies-other
Project description:ObjectiveProstaglandins (PGs) are considered universal mediators for the process of physiological parturition. This is based on observations that amniotic fluid concentrations of PGs are elevated prior to and during the onset of labor (mostly utilizing immunoassays). Distinguishing PGs from similarly structured molecules (i.e. prostamides; PG-EA) is difficult given the cross-reactivity of available antibodies and the chemical similarity between these compounds. Herein, this limitation was overcome by utilizing mass spectrometry to determine PG and PG-EA concentrations in amniotic fluid of women with spontaneous labor at term and in those with clinical chorioamnionitis (CHAM), the most common infection-related diagnosis made in labor and delivery units worldwide.Study designLiquid chromatography-tandem mass spectrometry (LC MS/MS) was used to determine the PG and PG-EA content in amniotic fluid samples of women with spontaneous labor at term with (n = 14) or without (n = 28) CHAM. Controls included women who delivered at term without labor (n = 10).ResultsPGE2, PGF2α, and 13,14-dihydro-15-keto-PGF2α (PGFM) were higher in amniotic fluid of women with spontaneous labor at term than in those without labor. PGE2, PGF2α, and PGFM were also higher in amniotic fluid of women with CHAM than in those without labor. However, PGE2-EA and PGF2α-EA were lower in amniotic fluid of women with CHAM than in those without CHAM. The ratios of PGE2 to PGE2-EA and PGF2α to PGF2α-EA were higher in amniotic fluid of women with spontaneous labor at term with or without CHAM than in those without labor; yet, the ratio of PGF2α to PGF2α-EA was greater in women with CHAM than in those without this clinical condition.ConclusionsSpontaneous labor at term with or without CHAM is characterized by elevated amniotic fluid concentrations of prostaglandins (PGE2, PGF2α, and PGFM) but not prostamides. Quantification of these products by LC MS/MSlc==may potentially be of utility in identifying their physiological functions relevant to parturition.SummaryProstaglandins (PGs) are critical for the onset and progression of labor. Structural similarities of PGs and prostamides (PG-EA) prevents their specific identification by immunoassay. We utilized LC MS/MS to determine PG and PG-EA content in amniotic fluid (AF) of women with spontaneous labor at term with or without CHAM and women who delivered at term without labor. Higher aamniotic ffluid PG levels were observed in women with spontaneous labor with and without CHAM compared to women delivering without labor. PG-EA levels in amniotic fluid of women with spontaneous labor and CHAM were lower than in women with spontaneous labor without CHAM but not those without labor. Ratios of PGs to PG-EAs were higher in AF of women with labor and CHAM compared to those without labor. Delineation of these products by LC MS/MS may potentially be of utility in identifying their physiological functions relevant to parturition.
| S-EPMC8314956 | biostudies-literature
Project description:Prior to and during the process of human labor, maternal circulating leukocytes infiltrate the maternal-fetal interface (choriodecidua) and become activated resembling choriodecidual leukocytes. Since, there is no evidence comparing maternal circulating and choriodecidual leukocytes, herein, we characterized their transcriptome and explored the biological processes enriched in choriodecidual leukocytes. From women undergoing spontaneous term labor we isolated circulating and choriodecidual leukocytes, performed microarray analysis (n?=?5) and qRT-PCR validation (n?=?9) and interaction network analysis with up-regulated genes. We found 270 genes up-regulated and only 17 genes down-regulated in choriodecidual leukocytes compared to maternal circulating leukocytes. The most up-regulated genes were CCL18, GPNMB, SEPP1, FN1, RNASE1, SPP1, C1QC, and PLTP. The biological processes enriched in choriodecidual leukocytes were cell migration and regulation of immune response, chemotaxis, and humoral immune responses. Our results show striking differences between the transcriptome of choriodecidual and maternal circulating leukocytes. Choriodecidual leukocytes are enriched in immune mediators implicated in the spontaneous process of labor at term.
| S-EPMC6358585 | biostudies-literature
Project description:ObjectiveTo evaluate the effect of histological chorioamnionitis (HCA) with a negative amniotic fluid (AF) culture on adverse pregnancy and neonatal outcomes and inflammatory status in the AF compartment in women with preterm labor or preterm premature rupture of membranes (PPROM).MethodsThis is a retrospective cohort study of 153 women diagnosed as having a preterm labor or PPROM (20-34 weeks) who delivered singleton gestations within 48 hours of amniocentesis. AF obtained through amniocentesis was cultured, and interleukin (IL)-6, IL-8, and metalloproteinase-9 (MMP-9) levels were determined. The placentas were examined histologically.ResultsThe prevalence of HCA with negative AF culture was 23.5% (36/153). The women with HCA but with a negative AF culture (group 2) and those with a positive AF culture (group 3) had a significantly lower mean gestational age at amniocentesis and delivery than those with a negative AF culture and without HCA (group 1). Women in group 3 had the highest levels of AF IL-6, IL-8, and MMP-9, followed by those in group 2, and those in group 1. Composite neonatal morbidity was significantly higher in groups 2 and 3 than in group 1, but this was no longer significant after adjusting for confounders caused mainly by the impact of gestational age.DiscussionIn the women who delivered preterm neonates, HCA with a negative AF culture was associated with increased risks of preterm birth, intense intra-amniotic inflammatory response, and prematurity-associated composite neonatal morbidity, and its risks are similar to the risk posed by positive AF culture.
| S-EPMC5344397 | biostudies-literature
Project description:Collectins, collagen-containing Ca(2+) dependent C-type lectins and a class of secretory proteins including SP-A, SP-D and MBL, are integral to immunomodulation and innate immune defense. In the present study, we aimed to investigate their placental transcript synthesis, labor associated differential expression and localization at feto-maternal interface, and their functional implication in spontaneous labor. The study involved using feto-maternal interface (placental/decidual tissues) from two groups of healthy pregnant women at term (≥ 37 weeks of gestation), undergoing either elective C-section with no labor ('NLc' group, n = 5), or normal vaginal delivery with spontaneous labor ('SLv' group, n = 5). The immune function of SP-D, on term placental explants, was analyzed for cytokine profile using multiplexed cytokine array. SP-A, SP-D and MBL transcripts were observed in the term placenta. The 'SLv' group showed significant up-regulation of SP-D (p = 0.001), and down-regulation of SP-A (p = 0.005), transcripts and protein compared to the 'NLc' group. Significant increase in 43 kDa and 50 kDa SP-D forms in placental and decidual tissues was associated with the spontaneous labor (p<0.05). In addition, the MMP-9-cleaved form of SP-D (25 kDa) was significantly higher in the placentae of 'SLv' group compared to the 'NLc' group (p = 0.002). Labor associated cytokines IL-1α, IL-1β, IL-6, IL-8, IL-10, TNF-α and MCP-1 showed significant increase (p<0.05) in a dose dependent manner in the placental explants treated with nSP-D and rhSP-D. In conclusion, the study emphasizes that SP-A and SP-D proteins associate with the spontaneous labor and SP-D plausibly contributes to the pro-inflammatory immune milieu of feto-maternal tissues.
| S-EPMC4193748 | biostudies-literature
Project description:Acute chorioamnionitis, frequently observed in preterm placentas, is a major risk factor for the development of infection and non-infection-related adverse perinatal outcomes. MicroRNAs play important roles in immune cell development and function as well as in the development of cancers and neurologic diseases. We sought to investigate the changes in microRNA-223 (miR-223) expression and the functional significance of the changes in miR-223 expression in foetal organs in the presence of acute chorioamnionitis. Using formalin-fixed, paraffin-embedded (FFPE) tissue samples from foetal or neonatal autopsy cases, which are the most practical option to study the changes in several organs simultaneously, miR-223 expression profiles in foetal thymus, lung and liver were compared between cases with and without acute chorioamnionitis. Total RNA was extracted from FFPE specimens and qRT-PCR was conducted. miR-223-3p expression levels in foetal thymus (2.55-fold), lung (1.93-fold) and liver (1.70-fold) were significantly higher in cases with acute chorioamnionitis than in those without. Transfection of pre-miR-223-3p in Jurkat cells and luciferase assay and ribonucleoprotein immunoprecipitation followed by qRT-PCR analysis confirmed the binding of miR-223 to the 3' untranslated region (3'UTR) of forkhead box O1 (FoxO1) mRNA and the regulation of FoxO1 by miR-223. We report for the first time that foetuses with inflammation in the chorioamniotic membranes show increased expression of miR-223 in the thymus, lung and liver. Furthermore, FoxO1 is a target of miR-223. These findings suggest that post-transcriptional regulation of genes by miR-223 is a component of the foetal inflammatory response, which has systemic consequences in the foetus.
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Project description:Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality and is not uncommonly associated with chorioamnionitis. We recently have demonstrated that the placenta harbors a unique microbiome with similar flora to the oral community. We also have shown an association of these placental microbiota with PTB, history of antenatal infection, and excess maternal weight gain. On the basis of these previous observations, we hypothesized that the placental membranes would retain a microbiome community that would vary in association with preterm birth and chorioamnionitis.In the current study, we aimed to examine the differences in the placental membrane microbiome in association with PTB in both the presence and absence of chorioamnionitis and/or funisitis using state-of-the-science whole-genome shotgun metagenomics.This was a cross-sectional analysis with 6 nested spontaneous birth cohorts (n = 9-15 subjects/cohort): Term gestations without chorioamnionitis, term with chorioamnionitis, preterm without chorioamnionitis, preterm with mild chorioamnionitis, preterm with severe chorioamnionitis, and preterm with chorioamnionitis and funisitis. Histologic analysis was performed with Redline's criteria, and inflammatory cytokines were analyzed in the cord blood. DNA from placental membranes was extracted from sterile swabs collected at delivery, and whole-genome shotgun sequencing was performed on the Illumina HiSeq platform. Filtered microbial DNA sequences were annotated and analyzed with MG-RAST (ie, Metagenomic Rapid Annotations using Subsystems Technology) and R.Subjects were assigned to cohorts on the basis of gestational age at delivery and independent scoring of histologic chorioamnionitis. We found that preterm subjects with severe chorioamnionitis and funisitis had increases in cord blood inflammatory cytokines. Of interest, although the placental membrane microbiome was altered in association with severity of histologic chorioamnionitis (permutational multivariate analysis of variance P = .005), there was no observable impact with either betamethasone or antibiotic treatment. In preterm subjects with chorioamnionitis, we found a high abundance of both urogenital and oral commensal bacteria. These alterations in the microbiome were accompanied by significant variation (P < .05) in microbial metabolic pathways important in the glucose-fed pentose phosphate pathway (term subjects), or glycerophopholipid metabolism, and the biosynthesis of the siderophore group nonribosomal peptides (preterm subjects).Consistent with ours and others previous findings, women who experienced spontaneous PTB harbor placental microbiota that further differed by severity of chorioamnionitis. Integrative metagenomic analysis revealed significant variation in distinct bacterial metabolic pathways, which we speculate may contribute to risk of preterm birth with and without severe chorioamnionitis.
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