Inflammatory Preterm Birth Research Articles

Nicotine ameliorates inflammatory mediators in RU486 induced preterm labor model through activating cholinergic anti-inflammatory pathway.

Preterm birth is a global public health threat. Inflammatory reaction is thought to mediate preterm birth. The role of nicotine, an anti-inflammatory agent that is mediated by cholinergic anti-inflammatory pathways (CAP), remains unclear in the pathogenesis. Pregnant rats were randomly divided into four groups (20 rats each): pregnant control group (P), RU486-treated group (PTL), RU486 and nicotine-treated group (PTL+N), RU486, nicotine and α-BGT treated group (PTL+N+A). Rats were administered RU486 (1.0mg/kg) by subcutaneous injection on gestational day (GD) 18 to establish PTL model. Subcutaneous injection of nicotine (1mg/kg) was administered daily from GD 16 to 18. α-BGT (1µg/kg) was administrated subcutaneously in two sessions and each session was 30min prior to nicotine. TNF-α, IL-1β, IL-4, IL-6, IL-10 in myometrium and serum were detected by Luminex. Macrophage infiltration and α7nAChR were detected by IHC. We established a RU486-induced preterm labor rat model. Preterm labor was associated with a striking upregulation inflammatory mediators and increased macrophage infiltration. Nicotine significantly prolonged gestation (P<0.05) and α-BGT treatment reversed the prolonged interval (P<0.05). The cytokines all markedly elevated at 12h, but deceased after delivery (P<0.05). The IL-1β and TNF-α in serum were significantly increased in PTL group vs P group (P<0.05), and decreased after nicotine treatment (P<0.05). The cytokines IL-1β, IL-4, IL-6, IL-10 and TNF-α in myometrium increased as the same trend as in serum. Nicotine treatment also downregulated the expression of α7nAChR in pregnant tissue. We confirmed the increased inflammation in preterm birth. Nicotine was able to down-regulate the inflammatory mediates and prolong the pregnant duration in PTL model, which might be induced by activating α7nAChR through CAP. This study provides a novel evidence supporting the future development of therapeutic target for preterm birth.

The Expression of IL-1β Correlates with the Expression of Galectin-3 in the Tissue at the Maternal-Fetal Interface during the Term and Preterm Labor.

The inflammatory processes that occur at the maternal-fetal interface are considered one of the factors that are responsible for preterm birth. The pro-inflammatory roles of the Gal-3-induced activation of NLRP3 inflammasome and the consecutive production of IL-1β have been described in several acute and chronic inflammatory diseases, but the role of this inflammatory axis in parturition has not been studied. The aim of this study was to analyze the protein expression of Gal-3, NLRP3, and IL-1β in the decidua, villi, and fetal membranes, and to analyze their mutual correlation and correlation with the clinical parameters of inflammation in preterm birth (PTB) and term birth (TB). The study included 40 women that underwent a preterm birth (gestational age of 25.0-36.6) and histological chorioamnionitis (PTB) and control subjects, 22 women that underwent a term birth (gestational age of 37.0-41.6) without histological chorioamnionitis (TB). An analysis of the tissue sections that were stained with anti- Gal-3, -NLRP3, and -IL-1β antibodies was assessed by three independent investigators. The expression levels of Gal-3 and IL-1β were significantly higher (p < 0.001) in the decidua, villi, and fetal membranes in the PTB group when they compared to those of the TB group, while there was no difference in the expression of NLRP3. A further analysis revealed that there was no correlation between the protein expression of NLRP3 and the expression of Gal-3 and IL-1β, but there was a correlation between the expression of Gal-3 and IL-1β in decidua (R = 0.401; p = 0.008), villi (R = 0.301; p = 0.042) and the fetal membranes (R = 0.428; p = 0.002) in both of the groups, PTB and TB. In addition, the expression of Gal-3 and IL-1β in decidua and the fetal membranes was in correlation with the parameters of inflammation in the maternal and fetal blood (C-reactive protein, leukocyte number, and fibrinogen). The strong correlation between the expression of Gal-3 and IL-1β in the placental and fetal tissues during labor indicates that Gal-3 may participate in the regulation of the inflammatory processes in the placenta, leading to increased production of IL-1β, a cytokine that plays the main role in both term and preterm birth.

Inflammation in preterm birth: Novel mechanism of preterm birth associated with innate and acquired immunity

Preterm birth (PB) is the most-frequent complication occurring during pregnancy, with a significant impact on neonatal morbidity and mortality. Chorioamnionitis (CAM), the neutrophil infiltration into chorioamniotic membranes, is a major cause of PB. However, several cases of PB have also been reported without apparent pathogenic infection or CAM. Such cases are now attributed to “sterile inflammation.” The concept of sterile inflammation has already attracted attention in various diseases, like cardiovascular diseases, diabetes, and autoimmune diseases; recently been discussed for obstetric complications such as miscarriage, PB, gestational hypertension, and gestational diabetes. Sterile inflammation is induced by alarmins, such as high-mobility group box 1 (HMGB1), interleukins (IL-33 and IL-1α), and S100 proteins, that are released by cellular damage without apparent pathogenic infection. These antigens are recognized by pattern-recognition receptors, expressed mainly on antigen-presenting cells of decidua, placenta, amnion, and myometrium, which consequently trigger inflammation. In reproduction, these alarmins are associated with the development of various pregnancy complications, including PB. In this review, we have summarized the development of PB related to acute CAM, chronic CAM, and sterile inflammation as well as proposed a new mechanism for PB that involves innate immunity, acquired immunity, and sterile inflammation.

早産と炎症

早産と炎症

Breaking Down the Barrier: The Role of Cervical Infection and Inflammation in Preterm Birth

Approximately 40% of cases of spontaneous preterm birth (sPTB) are associated with ascending intrauterine infections. The cervix serves as a physical and immunological gatekeeper, preventing the ascent of microorganisms from the vagina to the amniotic cavity. The cervix undergoes remodeling during pregnancy. It remains firm and closed from the start until the late third trimester of pregnancy and then dilates and effaces to accommodate the passage of the fetus during delivery. Remodeling proceeds appropriately and timely to maintain the pregnancy until term delivery. However, risk factors, such as acute and chronic infection and local inflammation in the cervix, may compromise cervical integrity and result in premature remodeling, predisposing to sPTB. Previous clinical studies have established bacterial (i.e., chlamydia, gonorrhea, mycoplasma, etc.) and viral infections (i.e., herpesviruses and human papillomaviruses) as risk factors of PTB. However, the exact mechanism leading to PTB is still unknown. This review focuses on: (1) the epidemiology of cervical infections in pregnant patients; (2) cellular mechanisms that may explain the association of cervical infections to premature cervical ripening and PTB; (3) endogenous defense mechanisms of the cervix that protect the uterine cavity from infection and inflammation; and (4) potential inflammatory biomarkers associated with cervical infection that can serve as prognostic markers for premature cervical ripening and PTB. This review will provide mechanistic insights on cervical functions to assist in managing cervical infections during pregnancy.

MiR‑199a‑3p suppresses cervical epithelial cell inflammation by inhibiting the HMGB1/TLR4/NF‑κB pathway in preterm birth.

Preterm birth (PTB) is the primary cause of neonatal mortality worldwide. Infection and inflammation are considered to be the primary causes of PTB. Cervical remodeling is an important step in the process of preterm delivery, and the destruction of the cervical epithelial barrier and inflammation are important triggers of cervical remodeling. The aim of the present study was to determine the effect and underlying mechanism of microRNA (miR)-199a-3p/high-mobility group box 1 protein (HMGB1) signaling in cervical epithelial inflammation in PTB. The results of this study revealed that miR-199a-3p was significantly decreased in cervical epithelial tissue samples from patients in both the preterm labor and preterm premature rupture of membrane groups. This decrease was also observed in tissue samples from a lipopolysaccharide (LPS)-induced PTB mouse model and in LPS-induced ectocervical and endocervical cells. Whereas, the expression of HMGB1 and toll-like receptor 4 (TLR4) was significantly increased, which was associated with the upregulation of interleukin (IL)-1β and tumor necrosis factor (TNF)-α expression. Furthermore, overexpression of miR-199a-3p significantly suppressed the expression and activation of HMGB1 and TLR4/NF-κB signaling, and decreased the levels of IL-1β and TNF-α in vitro and in vivo. Additionally, overexpression of HMGB1 and/or TLR4 reversed the anti-inflammatory effects of miR-199a-3p mimics in vitro and in vivo. These results indicate that miR-199a-3p acts as a negative inflammatory regulator in PTB by targeting HMGB1 to regulate the TLR4/NF-κB pathway.

PLACENTAL INFLAMMATION IN SPONTANEOUS PRETERM BIRTH AND NEONATAL OUTCOMES

Background: Preterm birth (PTB) can be classified as spontaneous or indicated. The complications of PTB can affect all systems and result in chronic physical and mental disabilities. Objective: The objective of the study was to assess the incidence of placental inflammation in PTB with and without preterm premature rupture of membranes (pPROM) and its effects on various neonatal outcomes. Materials and Methods: This prospective observational study was conducted in a tertiary hospital where all preterm neonates born by spontaneous onset vaginal delivery and cesarean section were included in the study. Neonates born to mothers having significant uterine anomalies, multiple gestations, and those with any major congenital anomalies were excluded from the study. Placentas were assessed for evidence of inflammation on histopathological examination. Correlation of placental inflammation with neonatal morbidity and mortality was also assessed. Results: The incidence of placental inflammation in spontaneous onset preterm births (sPTB) was found to be 29%. Most placentas showed Stage 1 chorioamnionitis (47%). Three placentas had evidence of fetal inflammatory response, of which one had early funisitis (Stage 1) and two had intermediate funisitis (Stage 2). Of the nine neonates who had features of sepsis (definite or probable), 4 (44.4%) had evidence of placental inflammation. No significant association was found between placental inflammation and other secondary outcomes such as duration of neonatal intensive care unit stay, neonatal mortality, requirement of phototherapy, and need for continuous positive airway pressure support. Conclusions: Placental inflammation was seen in almost one-third of cases of sPTB, of which 78% were without pPROM. Hence, sPTB irrespective of pPROM should be considered as indirect marker of ongoing inflammation.

Evidence of a gene-environment interaction of NODAL variants and inflammation in preterm birth.

NODAL has been implicated in timing of parturition and immune regulation. We investigated the relationship between NODAL polymorphisms, infection/inflammation, and preterm birth. For this secondary analysis, 613 women (189 preterm and 424 term) from the Montreal Prematurity Study were genotyped for NODAL polymorphisms and assessed for bacterial vaginosis and placental inflammation. NODAL polymorphisms were not associated with preterm birth. However, the rs2231947(C>T) variant allele was associated with increased risk for preterm birth among women with bacterial vaginosis (odds ratio: 2.76, 95% confidence interval: 1.12-6.85). Among women without placental inflammation, the rs1904589(A>G) variant allele was associated with increased risk of preterm birth (odds ratio: 1.31, 95% confidence interval: 1.02-1.70). Among women with placental inflammation, the rs10999338(C>T) variant allele was associated with reduced risk of preterm birth (odds ratio: 0.50, 95% confidence interval: 0.29-0.87). The effect of NODAL polymorphisms on preterm birth depends on maternal infection/inflammation status.

Molecular analysis of endometrial inflammation in preterm birth.

Spontaneous preterm birth (sPTB) represents the 35%-45% of all preterm birth (PTB) cases and its etiology is unknown. We investigated if the expression level of endometrial cytokines and angiogenetic factors is related to the onset of sPTB.Endometrial tissues from non-pregnant women who experienced sPTB and from non-pregnant women who did not experience sPTB were collected and examined for their expression profile. With this aim, the PCR Array analysis was performed and data were confirmed by Real-Time PCR. Differential gene expression measurements (pathological vs control tissues) showed a significant up-regulation for genes codifying for two angiogenetic factors known as connective tissue growth factor (CTGF), and coagulation factor III (F3). An increased level of expression was detected both for tyrosine kinase endothelial (TEK) and for transforming growth factor beta 2 (TGF-β2) genes but without reaching the statistical significance. The expression level of interleukin 10 receptor alpha (IL10RA) gene was slightly decreased in pathological group compared to control one but, as well as forTEK and TGF-β2 measurements, without reaching the statistical significance. Our work is the first to correlate the imbalance in endometrial district of non -pregnant women with sPTB. These data could suggest a new point of view whence to read sPTB. We need additional clinical and biological studies to clarify sPTB pathogenesis.

The relationship of circulating proteins in early pregnancy with preterm birth

Preterm birth (PTB) (< 37 completed weeks' gestation) is a pathological outcome of pregnancy and a major global health problem. Babies born preterm have an elevated risk for long-term adverse medical and neurodevelopmental sequelae. Substantial evidence implicates intrauterine infection and/or inflammation in PTB. However, these are often relatively late findings in the process, when PTB is inevitable. Identification of earlier markers of PTB may make successful intervention possible. Although select proteins, notably those related to theinflammatory pathways, have been associated with PTB, there has been a lack of research into the role of other protein pathways in the development of PTB. The purpose of this study was to investigate, using a previously described biomarker discovery approach, a subset of circulating proteins and their association with PTB focusing on samples from early pregnancy. The objectives of the study were as follows: (1) to perform a large-scale biomarker discovery, utilizing an innovative platform to identify proteins associated with preterm birth in plasma taken between 10 and 15 weeks' gestation and, (2) to determine which protein pathways are most strongly associated with preterm birth. To address these aims, we measured 1129 proteins in a plasma sample from early pregnancy using a multiplexed aptamer-based proteomic technology developed in Colorado by SomaLogic. Using a nested case-control approach, we measured proteins at a single time point in early pregnancy in 41 women who subsequently delivered preterm and 88 women who had term uncomplicated deliveries. We measured 1129 proteins using a multiplexed aptamer-based proteomic technology developed by SomaLogic. Logistic regressions and random forests were used to compare protein levels. The complement factors B and H and the coagulation factors IX and IX ab were the highest-ranking proteins distinguishing cases of preterm birth from term controls. The top 3 pathways associated with preterm birth were the complement cascade, the immune system, and the clotting cascade. Using a discovery approach, these data provide further confirmation that there is an association of immune- and coagulation-related events in early pregnancy with preterm birth. Thus, plasma protein profiles at 10-15 weeks of gestation are related to the development of preterm birth later in pregnancy.

The role of infection and inflammation in preterm birth

The role of infection and inflammation in preterm birth

282: Chorioamnionitis induced by intramniotic injection of IL1, LPS or Ureaplasma parvum is associated with an altered microbiome in a primate model of inflammatory preterm birth (PTB)

282: Chorioamnionitis induced by intramniotic injection of IL1, LPS or Ureaplasma parvum is associated with an altered microbiome in a primate model of inflammatory preterm birth (PTB)

436: Choriomanionitis induced by sterile LPS or IL1 associates with an altered microbiome in a primate model of inflammatory preterm birth

436: Choriomanionitis induced by sterile LPS or IL1 associates with an altered microbiome in a primate model of inflammatory preterm birth

Effect of interleukin-6 polymorphism on risk of preterm birth within population strata: a meta-analysis

BackgroundBecause of the role of inflammation in preterm birth (PTB), polymorphisms in and near the interleukin-6 gene (IL6) have been association study targets. Several previous studies have assessed the association between PTB and a single nucleotide polymorphism (SNP), rs1800795, located in the IL6 gene promoter region. Their results have been inconsistent and SNP frequencies have varied strikingly among different populations. We therefore conducted a meta-analysis with subgroup analysis by population strata to: (1) reduce the confounding effect of population structure, (2) increase sample size and statistical power, and (3) elucidate the association between rs1800975 and PTB.ResultsWe reviewed all published papers for PTB phenotype and SNP rs1800795 genotype. Maternal genotype and fetal genotype were analyzed separately and the analyses were stratified by population. The PTB phenotype was defined as gestational age (GA) < 37 weeks, but results from earlier GA were selected when available. All studies were compared by genotype (CC versus CG+GG), based on functional studies.For the maternal genotype analysis, 1,165 PTBs and 3,830 term controls were evaluated. Populations were stratified into women of European descent (for whom the most data were available) and women of heterogeneous origin or admixed populations. All ancestry was self-reported. Women of European descent had a summary odds ratio (OR) of 0.68, (95% confidence interval (CI) 0.51 – 0.91), indicating that the CC genotype is protective against PTB. The result for non-European women was not statistically significant (OR 1.01, 95% CI 0.59 - 1.75). For the fetal genotype analysis, four studies were included; there was no significant association with PTB (OR 0.98, 95% CI 0.72 - 1.33). Sensitivity analysis showed that preterm premature rupture of membrane (PPROM) may be a confounding factor contributing to phenotype heterogeneity.ConclusionsIL6 SNP rs1800795 genotype CC is protective against PTB in women of European descent. It is not significant in other heterogeneous or admixed populations, or in fetal genotype analysis.Population structure is an important confounding factor that should be controlled for in studies of PTB.

The role of inflammation in preterm birth—focus on periodontitis

It is universally accepted that acute inflammation is responsible for a substantial fraction of preterm births, particularly early cases. Much of this inflammation is caused by intrauterine infection. There is also evidence that infection and perhaps inflammation remote from the genitourinary tract can trigger preterm labour. Several studies have suggested that periodontitis during pregnancy increases the risk of preterm birth. Periodontitis may cause preterm birth by causing low-grade bacteraemia, which lodges in the decidua, chorion and amnion or by releasing endotoxin into the maternal circulation, which triggers intrauterine inflammation and preterm birth. Alternatively, it may release cytokines and other inflammatory products, which then trigger preterm labour. It is also conceivable that periodontitis might serve as a marker for other unhealthy behaviours, or immune hyperresponsiveness and that hyperresponsiveness to low-grade intrauterine infection itself might cause preterm birth. Currently, there are few data available to distinguish these possibilities. Such distinctions are important since they have clear implications for whether treatment of periodontitis might reduce the incidence of preterm birth. Several clinical trials of treatment of periodontitis are continuing, but until their results are known there is currently little evidence that treatment of periodontitis during pregnancy reduces the incidence of preterm birth.

Intra-Amniotic Infection and Inflammation in Preterm Birth – is Bacteria Always the Connection?: Commentary on the article by Miralles et al. on page 570

Intra-Amniotic Infection and Inflammation in Preterm Birth – is Bacteria Always the Connection?: Commentary on the article by Miralles et al. on page 570

Tumor necrosis factor-α polymorphism -863 in mother-infant pairs and inflammatory preterm birth

Tumor necrosis factor-α polymorphism -863 in mother-infant pairs and inflammatory preterm birth