TLR-4-Dependent and -Independent Mechanisms of Fetal Brain Injury in the Setting of Preterm Birth

Breen, Kelsey; Brown, Amy G.; Burd, Irina; Chai, Jinghua; Friedman, Alexander; Elovitz, Michal A.

doi:10.1177/1933719112438439

Cited by 29 publications

(22 citation statements)

References 102 publications

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“…MIAC and subclinical intra‐amniotic inflammation are implicated in at least one‐third of the cases of spontaneous preterm labor and delivery . Furthermore, intra‐amniotic infection has been recognized as predisposing to cerebral palsy and chronic lung disease . However, with the exception of asymptomatic bacteriuria, prophylactic antibiotic treatment has not been successful in the prevention of preterm birth, and some have claimed that it may increase the rate of preterm delivery …”

Section: Resultsmentioning

confidence: 99%

A Novel Molecular Microbiologic Technique for the Rapid Diagnosis of Microbial Invasion of the Amniotic Cavity and Intra‐Amniotic Infection in Preterm Labor with Intact Membranes

Romero

Miranda

Chaiworapongsa

et al. 2014

American J Rep Immunol

183

197

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Objective The major challenges in using amniotic fluid (AF) cultivation techniques to diagnose microbial invasion of the amniotic cavity (MIAC) are: 1) several days are typically required to obtain results, and 2) many organisms implicated in the pathogenesis of human disease are difficult to culture. Here, we compare the performance of AF culture with a novel technique for the diagnosis of MIAC that can provide results within eight hours by combining broad-range real-time polymerase chain reaction with electrospray ionization mass spectrometry (PCR/ESI-MS) to identify and quantify genomic material from bacteria and viruses in AF. Methods AF samples obtained by transabdominal amniocentesis from 142 women with preterm labor (PTL) and intact membranes were analyzed using cultivation techniques (aerobic, anaerobic and genital mycoplasmas) as well as PCR/ESI-MS. The prevalence and relative magnitude of intra-amniotic inflammation [AF Interleukin 6 (IL-6) concentration ≥ 2.6 ng/mL], acute histologic chorioamnionitis, spontaneous preterm delivery, and perinatal mortality were examined according to the results of these two tests. Results 1) The prevalence of MIAC in patients with preterm labor and intact membranes was 7% using standard cultivation techniques and 12% using PCR/ESI-MS; 2) seven of ten patients with positive AF culture also had positive PCR/ESI-MS [≥17 genome equivalents per PCR reaction well (GE/well)] 3) patients with positive PCR/ESI-MS (≥17 GE/well) and negative AF cultures had significantly higher rates of intra-amniotic inflammation and histologic acute chorioamnionitis, shorter intervals to delivery [median (interquartile range-IQR)], and offspring at higher risk of perinatal mortality, than women with both tests negative [90% (9/10) vs. 32% (39/122); (p<0.001); 70% (7/10) vs. 35% (39/112); (p=0.04); 1 (IQR: <1 – 2) days vs. 25 (IQR: 5 – 51) days; (p=0.002); OR: 5.6; 95% CI: 1.4 – 22, respectively]; 5) there were no significant differences in these factors between patients with positive PCR/ESI-MS (≥17 GE/well) who had negative AF cultures compared to those with positive AF cultures; and 6) PCR/ESI-MS detected genomic material from viruses in two patients (1.4%). Conclusion 1) Rapid diagnosis of intra-amniotic infection is possible using PCR/ESI-MS, which can provide results within 8 hours; 2) the combined use of biomarkers of inflammation and PCR/ESI-MS allows for the rapid identification of specific bacteria and viruses in women with preterm labor and intra-amniotic infection; and 3) this approach may allow for administration of timely and specific interventions to reduce morbidity attributed to infection-induced preterm birth.

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Section: Resultsmentioning

confidence: 99%

A Novel Molecular Microbiologic Technique for the Rapid Diagnosis of Microbial Invasion of the Amniotic Cavity and Intra‐Amniotic Infection in Preterm Labor with Intact Membranes

Romero

Miranda

Chaiworapongsa

et al. 2014

American J Rep Immunol

183

197

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“…CD1 pregnant dams Charles River were used for this study. Pregnant dams were subjected to a well‐established model of IUI as per a previously described protocol on embryonic day 17 (E17) . Mice were anesthetized with isoflurane (Baxter # NDC 10019‐360‐60) before undergoing a mini‐laparotomy.…”

Section: Methodsmentioning

confidence: 99%

“…Pregnant dams were subjected to a well-established model of IUI as per a previously described protocol on embryonic day 17 (E17). [30][31][32] Mice were anesthetized with isoflurane (Baxter # NDC 10019-360-60) before undergoing a mini-laparotomy. After dressing the abdominal area, a 1.5-cm midline incision was performed in the lower abdominal wall.…”

Section: Animal Preparationmentioning

confidence: 99%

Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation‐induced oxidative stress in a mouse model

Lee

Shin

et al. 2019

Journal of Pineal Research

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Melatonin has been shown to reduce oxidative stress and mitigate hypercoagulability. We hypothesized that maternally administered melatonin may reduce placental oxidative stress and hypercoagulability associated with exposure to intrauterine inflammation (IUI) and consequently improve fetoplacental blood flow and fetal sequelae. Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro‐inflammatory mediators was significantly increased in L compared to C and ML. The systolic/diastolic ratio, resistance index, and pulsatility index in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared with other groups when analyzed by Doppler ultrasonography. The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro‐inflammatory mediators was significantly increased in L compared to C and ML. Vascular endothelial damage and thrombi formation, as evidenced by fibrin deposits, were similarly increased in L compared to other groups. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise, and fetal neuroinflammation induced by IUI through its antioxidant properties.

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“…53,54 Since IL-1β has the potential to be damaging, its regulation is tightly controlled. Indeed, IL-1β is an important mediator of preterm birth 102,103,104,105 , and perinatal brain injury, 106,107,108,109 and can trigger the production of other pro-inflammatory cytokines and chemokines through the IL-1 receptor in a similar manner to TLRs. 55 Indeed delivery of a synthetic peptide to pregnant mice that is a selective IL-1 receptor modulator, delays IL-1β delays and LPS-induced preterm birth.…”

Section: Review Of Placental Development and Function In The Contementioning

confidence: 99%

“…Indeed, a TLR4 antagonist prevented LPS-induced preterm uterine contractility in non-human primates 100 and knockout mice for TLR or associated adapter proteins are resistant to microbial and PAMP-induced preterm birth. 83,101 Similarly, since IL-1β is a mediator of preterm birth 102,103,104,105 and fetal brain injury 106,107,108,109 studies have focused on using IL-1 receptor antagonists or selective IL-1 receptor modulators to prevent these adverse outcomes. 110,111 Thus, preventing the upstream induction of IL-1β by inhibiting placental inflammasome activity may also serve as a potential target for preventing adverse pregnancy outcomes.…”

Section: Review Of Placental Development and Function In The Contementioning

confidence: 99%

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

Ilekis

Tsilou

Fisher

et al. 2016

American Journal of Obstetrics and Gynecology

233

167

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Although much progress is being made in understanding the molecular pathways in the placenta involved in the pathophysiology of pregnancy related disorders, a significant gap exists in utilizing this information for developing new drug therapies to improve pregnancy outcome. On March 5–6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a two day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given in the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of this workshop. A broad number of topics were covered ranging from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and non-infectious agents. Research findings in these areas will be critical for formulating developing future treatments and developing therapies for the prevention of a number of pregnancy disorders of placental origin including preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented summarizing ongoing clinical efforts in the U.S. and in Europe testing novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy using virally-delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by enhancing nutrient transport to the fetus by modulating their placental transporters, as well as targeting placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined especially in the context of the unique pharmacokinetic properties of pregnancy, as well as the hurdles and pitfalls of translating research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy using macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community needs to change their thinking of the pregnant women and her fetus as a vulnerable patient population for which drug development should be avoided, but rather thought of as a deprived population in need of more effective therapeutic interventions.

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TLR-4-Dependent and -Independent Mechanisms of Fetal Brain Injury in the Setting of Preterm Birth

Cited by 29 publications

References 102 publications

A Novel Molecular Microbiologic Technique for the Rapid Diagnosis of Microbial Invasion of the Amniotic Cavity and Intra‐Amniotic Infection in Preterm Labor with Intact Membranes

A Novel Molecular Microbiologic Technique for the Rapid Diagnosis of Microbial Invasion of the Amniotic Cavity and Intra‐Amniotic Infection in Preterm Labor with Intact Membranes

Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation‐induced oxidative stress in a mouse model

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

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