Intra‐Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth

Gomez‐Lopez, Nardhy; Romero, Roberto; Plazyo, Olesya; Panaitescu, Bogdan; Furcron, Amy Eunice; Miller, Derek; Roumayah, Tamara; Flom, Emily; Hassan, Sonia S.

doi:10.1111/aji.12443

Cited by 114 publications

(104 citation statements)

References 19 publications

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“…In some of the cases, however, bacteria were not detectable by conventional microbiological techniques or live/dead staining, which is able to detect genital mycoplasmas 46 . These data suggest that fetal neutrophils invade the amniotic cavity in response to monomicrobial and polymicrobial infections as well as in the setting of sterile intra-amniotic inflammation, an inflammatory process induced by alarmins or danger signals 36-39, 68, 97, 98 . In either scenario, fetal neutrophils possibly invade the amniotic cavity by migrating from the chorionic plate or the fetus itself (e.g.…”

Section: Discussionmentioning

confidence: 87%

Are amniotic fluid neutrophils in women with intraamniotic infection and/or inflammation of fetal or maternal origin?

Gomez‐Lopez

Romero

et al. 2017

American Journal of Obstetrics and Gynecology

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101

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Background Neutrophils are the most abundant white blood cells found in the amniotic cavity of women with intra-amniotic infection and/or inflammation. The current belief is that these neutrophils are of fetal origin. However, abundant neutrophils have been found in the amniotic fluid of women with a severe acute maternal inflammatory response but without a fetal inflammatory response in the placenta, suggesting that these innate immune cells can also be of maternal origin or a mixture of both fetal and maternal neutrophils. Objectives To investigate the origin of amniotic fluid neutrophils from women with intra-amniotic infection and/or inflammation, and to correlate these findings with acute histologic maternal and fetal inflammatory responses in the placenta. Study Design Amniotic fluid was collected from 15 women with suspected intra-amniotic infection and/or inflammation (positive microbiological cultures and/or interleukin (IL)-6 concentrations≥2.6 ng/mL). Amniotic fluid neutrophils were purified by fluorescence-activated cell sorting, DNA was extracted, and DNA fingerprinting was performed. DNA fingerprinting was also performed in the umbilical cord and maternal blood DNA. Fluorescence in situ hybridization (FISH) was assayed in women with male neonates. Blinded placental histopathological evaluations were conducted. Results 1) DNA fingerprinting revealed that 43% (6/14) of the women who underwent a single amniocentesis had mostly fetal neutrophils in the amniotic fluid; 2) DNA fingerprinting showed that 36% (5/14) of the women who underwent a single amniocentesis had predominantly maternal neutrophils in the amniotic fluid; 3) DNA fingerprinting indicated that 21% (3/14) of the women who underwent a single amniocentesis had an evident mixture of fetal and maternal neutrophils in the amniotic fluid; 4) DNA fingerprinting revealed that a woman who underwent two amniocenteses (patient #15) had fetal neutrophils first, and as infection progressed, abundant maternal neutrophils invaded the amniotic cavity ; 5) FISH confirmed DNA fingerprinting results by showing that both fetal and maternal neutrophils are present in the amniotic fluid; 6) Most of the women who had predominantly amniotic fluid neutrophils of fetal origin at the time of collection delivered extremely preterm neonates [71% (5/7)]; 7) All of the women who had predominantly amniotic fluid neutrophils of maternal origin at the time of collection delivered term or late preterm neonates [100% (6/6)]; 8) Two of the women who had an evident mixture of fetal and maternal neutrophils in the amniotic fluid at the time of collection delivered extremely preterm neonates [67% (2/3)], and the third woman delivered a term neonate [33% (1/3)]; and 9) Most of the women included in this study presented acute maternal and fetal inflammatory responses in the placenta [87 % (13/15)]. Conclusion Amniotic fluid neutrophils can be either predominantly of fetal or maternal origin, or a mixture of both fetal and maternal origin, in women with intra-amniotic inf...

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Section: Discussionmentioning

confidence: 87%

Are amniotic fluid neutrophils in women with intraamniotic infection and/or inflammation of fetal or maternal origin?

Gomez‐Lopez

Romero

et al. 2017

American Journal of Obstetrics and Gynecology

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101

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“…However, these models do not reproduce the most common cases observed in clinical situation in which infection is not detectable but markers of inflammation are still present. Recently, animal models were developed first using fetal DNA as a stimuli leading to inflammation and fetal demise40 whereas another group used high-mobility group box 1 (HMGB1) administration in the amniotic fluid which induced preterm labor41. Both HMGB1 and cffDNA were shown by ourselves and others to be elevated in pregnancy pathologies14–18 in association with placental dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Uric Acid Crystals Induce Placental Inflammation and Alter Trophoblast Function via an IL-1–Dependent Pathway: Implications for Fetal Growth Restriction

Brien

Duval

Palacios

et al. 2017

The Journal of Immunology

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Excessive placental inflammation is associated with several pathological conditions, including stillbirth and fetal growth restriction (FGR). While infection is a known cause of inflammation, a significant proportion of pregnancies have evidence of inflammation without any detectable infection. Inflammation can also be triggered by endogenous mediators, called damage associated molecular pattern (DAMPs) or alarmins. One of these DAMPs, uric acid is increased in the maternal circulation in pathological pregnancies and is a known agonist of the Nlrp3 inflammasome and inducer of inflammation. However its effects within the placenta and on pregnancy outcome remain largely unknown. We found that uric acid crystals (monosodium urate, MSU, crystals) induces a pro-inflammatory profile in isolated human term cytotrophoblast cells, with a predominant secretion of IL-1β and IL-6, a result confirmed in human term placental explants. Pro-inflammatory effects of MSU crystals were shown to be IL-1-dependent using a caspase-1 inhibitor (inhibits IL-1 maturation) and IL-1Ra (inhibits IL-1 signaling). The pro-inflammatory effect of MSU crystals was accompanied by trophoblast apoptosis and decreased syncytialisation. Correspondingly, administration of MSU crystals to rats during late gestation induced placental inflammation and was associated with fetal growth restriction. These results make a strong case for an active pro-inflammatory role of MSU crystals at the maternal-fetal interface in pathological pregnancies, and highlight a key mediating role of IL-1. Furthermore, our study describes a novel in vivo animal model of non-infectious inflammation during pregnancy, which is triggered by MSU crystals and leads to reduced fetal growth.

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“…Particularly, the high-mobility group box-1 (HMGB1, a prototypical alarmin 93, 94 ) protein can induce NET formation via TLR4 95 , which is the sensor molecule for lipopolysaccharide from Gram negative bacteria 96 . The fact that HMGB1 induces NETs is relevant since: (1) amniotic fluid HMGB1 concentrations are higher in women with intra-amniotic infection 97 or clinical chorioamnionitis 98 than in those without these clinical conditions; (2) patients with sterile intra-amniotic inflammation and high amniotic fluid HMGB1 concentrations delivered earlier than those with low concentrations of this alarmin 85 ; (3) the intra-amniotic administration of HMGB1 induces preterm labor and birth in mice 99 ; and (4) the chorioamniotic membranes from women who underwent spontaneous preterm labor releases high concentrations of HMGB1 100 . Alarmin-induced NETs can exacerbate immune responses by directly causing tissue damage 92 .…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps in acute chorioamnionitis: A mechanism of host defense

Gomez‐Lopez

Romero

Leng

et al. 2017

Am J Reprod Immunol

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Problem Neutrophil extracellular traps (NETs) were recently described as a mechanism for microbial killing in the amniotic cavity of women with intra-amniotic infection. Such a clinical condition can result in acute chorioamnionitis, a placental lesion characterized by the infiltration of maternal neutrophils in the chorioamniotic membranes. Herein, we investigated whether these infiltrating neutrophils form NETs in the chorioamniotic membranes from women who underwent spontaneous term or preterm labor with acute chorioamnionitis. Method of Study Chorioamniotic membrane samples were collected from women who underwent spontaneous term or preterm labor with acute chorioamnionitis (n=10 each). Controls included chorioamniotic membrane samples from women who delivered at term or preterm with or without labor, in the absence of acute chorioamnionitis (n=10 each). NETs were visualized and semi-quantified in the chorioamniotic membranes by using antibodies against neutrophil elastase and histone H3, in combination with DAPI staining. Results NETs were abundant in the chorioamniotic membranes from women who underwent spontaneous term or preterm labor with acute chorioamnionitis. NETs were rarely found, or not visualized at all, in the chorioamniotic membranes from women who delivered at term or preterm with or without labor, in the absence of acute chorioamnionitis. Conclusion NETs are abundant in the chorioamniotic membranes from women who underwent spontaneous term or preterm labor with acute chorioamnionitis. These findings suggest that chorioamniotic neutrophils can form NETs as a mechanism of host defense against infection or danger signals.

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Intra‐Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth

Cited by 114 publications

References 19 publications

Are amniotic fluid neutrophils in women with intraamniotic infection and/or inflammation of fetal or maternal origin?

Are amniotic fluid neutrophils in women with intraamniotic infection and/or inflammation of fetal or maternal origin?

Uric Acid Crystals Induce Placental Inflammation and Alter Trophoblast Function via an IL-1–Dependent Pathway: Implications for Fetal Growth Restriction

Neutrophil extracellular traps in acute chorioamnionitis: A mechanism of host defense

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