MicroRNA‐transcriptome networks in whole blood and monocytes of women undergoing preterm labour

Preterm birth is attributed to neonatal morbidity as well as cognitive and physiological challenges. We have previously identified significant differences in mRNA expression in whole blood and monocytes, as well as differences in miRNA concentration in blood plasma, extracellular vesicles (EV) and EV‐depleted plasma in women undergoing spontaneous preterm labour (sPTL). The goal of this analysis was to identify differences in miRNA expression within whole blood (WB) and peripheral monocytes (PM) from the same population of women undergoing sPTL compared with non‐labouring controls matched by gestational age. We performed single‐end small RNA sequencing in whole blood and peripheral monocytes from women undergoing sPTL with active contractions (24‐34 weeks of gestation, N = 15) matched for gestational age to healthy pregnant non‐labouring controls (>37 weeks gestation, N = 30) who later delivered at term as a part of the Ontario Birth Study (Toronto, Ontario CA). We identified significant differences in expression of 16 miRNAs in PMs and nine miRNAs in WB in women undergoing sPTL. In PMs, these miRNAs were predicted targets of 541 genes, including 28 previously associated with sPTL. In WB, miRNAs were predicted to target 303 genes, including nine previously associated with sPTL. These genes were involved in a variety of immune pathways, including interleukin‐2 signalling. This study is the first to identify changes in miRNA expression in WB and PMs of women undergoing sPTL. Our results shed light on potential mechanisms by which miRNAs may play a role in mediating systemic inflammatory response in pregnant women that deliver prematurely.     

Comparison of dermal vs internal light administration in human lungs using the TDLAS‐GASMAS technique—Phantom studies

Oxygen and water vapor content, in the lungs of a 3D‐printed phantom model based on CT‐images of a preterm infant, is evaluated using Tunable Diode Laser Absorption Spectroscopy (TDLAS) in Gas in Scattering Media Absorption Spectroscopy (GASMAS), that is, the TDLAS‐GASMAS technique. Oxygen gas is detected through an absorption line near 764 nm and water vapor through an absorption line near 820 nm. A model with a lung containing interior structure is compared to a model with a hollow lung. Compared to the model with the hollow lung, both the mean absorption path length and the transmitted intensity are found to be lower for the model with the structured lung. A new approach, where laser light is delivered internally into the model through an optical fiber, is compared to dermal light administration, that is, illumination onto the skin, for the model with structure inside the lung. The internal light administration generally resulted in larger gas absorption, and higher signal‐to‐noise ratios, compared to the dermal light administration. The results from the phantom measurements show great promise for the internal illumination approach and a natural next step would be to investigate it further in clinical studies.     

母胎界面免疫微环境在分娩启动和早产发生中的作用和机制

人类妊娠维持和分娩启动,与母胎界面免疫微环境的动态平衡密切相关。妊娠早期,母胎界面丰富的血供和免疫细胞相互作用营造的免疫耐受微环境是胚胎着床的关键;临近分娩时,原位或招募的免疫细胞在母胎界面局部形成炎性反应环境,促使胎儿从母体排出。因此,母胎界面免疫微环境调控着妊娠和分娩的各个环节,其平衡紊乱或异常会导致流产或早产的发生。本文就母胎界面几种重要的免疫细胞在分娩启动及早产发生中的作用和机制加以综述。     

Identification of a Feed-Forward Loop Between 15(S)-HETE and PGE2 in Human Amnion at Parturition

Human parturition is associated with massive arachidonic acid (AA) mobilization in the amnion, indicating that large amounts of AA-derived eicosanoids are required for parturition. Prostaglandin E2 (PGE2) synthesized from the cyclooxygenase (COX) pathway is the best characterized AA-derived eicosanoid in the amnion which plays a pivotal role in parturition. The existence of any other pivotal AA-derived eicosanoids involved in parturition remains elusive. Here, we screened such eicosanoids in human amnion tissue with AA-targeted metabolomics and studied their role and synthesis in parturition by using human amnion fibroblasts and a mouse model. We found that lipoxygenase (ALOX) pathway-derived 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) and its synthetic enzymes ALOX15 and ALOX15B were significantly increased in human amnion at parturition. Although 15(S)-HETE is ineffective on its own, it potently potentiated the activation of NF-κB by inflammatory mediators including lipopolysaccharide, interleukin-1β, and serum amyloid A1, resulting in the amplification of COX-2 expression and PGE2 production in amnion fibroblasts. In turn, we determined that PGE2 induced ALOX15/15B expression and 15(S)-HETE production through its EP2 receptor-coupled PKA pathway, thereby forming a feed-forward loop between 15(S)-HETE and PGE2 production in the amnion at parturition. Our studies in pregnant mice showed that 15(S)-HETE injection induced preterm birth with increased COX-2 and PGE2 abundance in the fetal membranes and placenta. Conclusively, 15(S)-HETE is identified as another crucial parturition-pertinent AA-derived eicosanoid in the amnion, which may form a feed-forward loop with PGE2 in parturition. Interruption of this feed-forward loop may be of therapeutic value for the treatment of preterm birth.     

Human milk nutrient fortifiers alter the developing gastrointestinal microbiota of very-low-birth-weight infants

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Altered lung development in bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is the main respiratory sequela of extreme prematurity. Its pathophysiology is complex, involving interactions between host and environment, likely to be significantly influenced by genetic factors. Thus, the clinical presentation and histological lesions have evolved over time, along with the reduction in neonatal injuries, and the care of more immature children. Impaired alveolar growth, however, is a lesion consistently observed in BPD, such that it is a key feature in BPD, and is even the dominant characteristic of the so‐called “new” forms of BPD. This review describes the key molecular pathways that are believed to be involved in the genesis of BPD. Much of our understanding is based on animal models, but this is increasingly being enriched by genetic approaches, and long‐term respiratory functional studies. Birth Defects Research (Part A) 100:158–167, 2014. © 2014 Wiley Periodicals, Inc.     

DNA methylation provides insight into intergenerational risk for preterm birth in African Americans

African Americans are at increased risk for spontaneous preterm birth (PTB). Though PTB is heritable, genetic studies have not identified variants that account for its intergenerational risk, prompting the hypothesis that epigenetic factors may also contribute. The objective of this study was to evaluate DNA methylation from maternal leukocytes to identify patterns specific to PTB and its intergenerational risk. DNA from peripheral leukocytes from African American women that delivered preterm (24–34 weeks; N = 16) or at term (39–41 weeks; N = 24) was assessed for DNA methylation using the HumanMethylation450 BeadChip. In maternal samples, 17,829 CpG sites associated with PTB, but no CpG site remained associated after correction for multiple comparisons. Examination of paired maternal-fetal samples identified 5,171 CpG sites in which methylation of maternal samples correlated with methylation of her respective fetus (FDR < 0.05). These correlated sites were enriched for association with PTB in maternal leukocytes. The majority of correlated CpG sites could be attributed to one or more genetic variants. They were also significantly more likely to be in genes involved in metabolic, cardiovascular, and immune pathways, suggesting a role for genetic and environmental contributions to PTB risk and chronic disease. The results of this study may provide insight into the factors underlying intergenerational risk for PTB and its consequences.     

Bilirubin and oxidative stress in term and preterm infants

Hyperbilirubinemia is the most frequent clinical problem neonatologists must deal with during the newborn period. It has been suggested that bilirubin is involved in the balance between antioxidant and pro-oxidant agents due to its antioxidant properties. However, the relevance of these effects in vivo in term and preterm infants is still debated. We performed a literature review of studies that investigated the association between total serum bilirubin (TSB) and oxidative stress in newborn infants. We found that studies in term infants give contradictory results, while studies in preterm infants suggest that the TSB increase is associated with an oxidative stress increase due to concurrent factors other than bilirubin level, such as heme oxygenase (HO) activity. Moreover, it could be speculated that low physiologic TSB values are associated with antioxidant effects, while high pathologic TSB values are associated with pro-oxidant effects. Literature data do not allow the establishment of whether if the antioxidant properties of bilirubin are important from a clinical point of view and can affect the outcome in ill infants.     

A developmental shift in habituation to pain in human neonates

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