Browsing by Author "Demery-Poulos, Catherine"

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    Clarithromycin prevents preterm birth and neonatal mortality by dampening alarmin-induced maternal–fetal infammation in mice
    (2022) Galaz, José; Romero, Roberto; Arenas-Hernandez, Marcia; Farías Jofré, Marcelo Enrique; Motomura, Kenichiro; Liu, Zhenjie; Kawahara, Naoki; Demery-Poulos, Catherine; Liu, Tzu N.; Padron, Justin; Panaitescu, Bogdan; Gomez-Lopez, Nardhy
    Background: One of every four preterm neonates is born to a woman with sterile intra-amniotic inflammation (inflammatory process induced by alarmins); yet, this clinical condition still lacks treatment. Herein, we utilized an established murine model of sterile intra-amniotic inflammation induced by the alarmin high-mobility group box-1 (HMGB1) to evaluate whether treatment with clarithromycin prevents preterm birth and adverse neonatal outcomes by dampening maternal and fetal inflammatory responses. Methods: Pregnant mice were intra-amniotically injected with HMGB1 under ultrasound guidance and treated with clarithromycin or vehicle control, and pregnancy and neonatal outcomes were recorded (n = 15 dams each). Additionally, amniotic fluid, placenta, uterine decidua, cervix, and fetal tissues were collected prior to preterm birth for determination of the inflammatory status (n = 7–8 dams each). Results: Clarithromycin extended the gestational length, reduced the rate of preterm birth, and improved neonatal mortality induced by HMGB1. Clarithromycin prevented preterm birth by interfering with the common cascade of parturition as evidenced by dysregulated expression of contractility-associated proteins and inflammatory mediators in the intra-uterine tissues. Notably, clarithromycin improved neonatal survival by dampening inflammation in the placenta as well as in the fetal lung, intestine, liver, and spleen. Conclusions: Clarithromycin prevents preterm birth and improves neonatal survival in an animal model of sterile intra-amniotic inflammation, demonstrating the potential utility of this macrolide for treating women with this clinical condition, which currently lacks a therapeutic intervention.
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    Defining a role for Interferon Epsilon in normal and complicated pregnancies
    (2022) Miller, Derek; Romero, Roberto; Kacerovsky, Marian; Musilova, Ivana; Galaz, Jose; Garcia-Flores, Valeria; Xu, Yi; Pusod, Errile; Demery-Poulos, Catherine; Gutierrez-Contreras, Pedro; Ning Liu, Tzu; Jung, Eunjung; Theis, Kevin R.; Coleman, Lanetta A.; Gomez-Lopez, Nardhy
    Interferon epsilon (IFNe) is a recently described cytokine that is constitutively expressed in the female repro-ductive tract. However, the role of this hormonally regulated cytokine during human pregnancy is poorly un-derstood. Moreover, whether IFNe participates in host immune response against bacteria-driven intra-amniotic infection or cervical human papillomavirus infection during pregnancy is unknown. Herein, using a unique set of human samples derived from multiple study cohorts, we aimed to uncover the role of IFNe in normal and complicated pregnancies. We showed that IFNe is expressed in the myometrium, cervix, and chorioamniotic membranes, and may therefore represent a constitutive element of host defense mechanisms in these tissues during pregnancy. The expression of IFNe in the myometrium and cervix appeared greater in late gestation than in mid-pregnancy, but did not seem to be impacted by labor. Notably, concentrations of IFNe in amniotic fluid, but not cervical fluid, were increased in a subset of women undergoing spontaneous preterm labor with intra-amniotic infection, indicating that IFNe could participate in anti-microbial responses in the amniotic cavity. However, stimulation with Ureaplasma parvum and/or lipopolysaccharide did not enhance IFNE expression by amnion epithelial or cervical cells in vitro, implicating alternative sources of this cytokine during intra-amniotic or cervical infection, respectively. Collectively, our results represent the first characterization of IFNe expression by human reproductive and gestational tissues during normal pregnancy and suggest a role for this cytokine in intra-amniotic infection leading to preterm birth.
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    Pregnancy imparts distinct systemic adaptive immune function
    (WILEY, 2022) Demery-Poulos, Catherine; Romero, Roberto; Xu, Yi; Arenas-Hernandez, Marcia; Miller, Derek; Tao, Li; Galaz, Jose; Farias-Jofre, Marcelo; Bhatti, Gaurav; Garcia-Flores, Valeria; Seyerle, Megan; Tarca, Adi L.; Gomez-Lopez, Nardhy
    Problem Pregnancy represents a state of systemic immune activation that is primarily driven by alterations in circulating innate immune cells. Recent studies have suggested that cellular adaptive immune components, T cells and B cells, also undergo changes throughout gestation. However, the phenotypes and functions of such adaptive immune cells are poorly understood. Herein, we utilized high-dimensional flow cytometry and functional assays to characterize T-cell and B-cell responses in pregnant and non-pregnant women. Methods Peripheral blood mononuclear cells from pregnant (n = 20) and non-pregnant (n = 25) women were used for phenotyping of T-cell and B-cell subsets. T-cell proliferation and B-cell activation were assessed by flow cytometry after in vitro stimulation, and lymphocyte cytotoxicity was evaluated by using a cell-based assay. Statistical comparisons were performed with linear mixed-effects models. Results Pregnancy was associated with modestly enhanced basal activation of peripheral CD4(+) T cells. Both CD4(+) and CD8(+) T cells from pregnant women showed increased activation-induced proliferation; yet, a reduced proportion of these cells expressed activation markers compared to non-pregnant women. There were no differences in peripheral lymphocyte cytotoxicity between study groups. A greater proportion of B cells from pregnant women displayed memory-like and activated phenotypes, and such cells exhibited higher activation following stimulation. Conclusion Maternal circulating T cells and B cells display distinct responses during pregnancy. The former may reflect the unique capacity of T cells to respond to potential threats without undergoing aberrant activation, thereby preventing systemic inflammatory responses that can lead to adverse perinatal consequences.
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    Pregnancy tailors endotoxin-induced monocyte and neutrophil responses in the maternal circulation
    (SPRINGER BASEL AG, 2022) Farias-Jofre, Marcelo; Romero, Roberto; Galaz, Jose; Xu, Yi; Tao, Li; Demery-Poulos, Catherine; Arenas-Hernandez, Marcia; Bhatti, Gaurav; Liu, Zhenjie; Kawahara, Naoki; Kanninen, Tomi; Shaffer, Zachary; Chaiworapongsa, Tinnakorn; Theis, Kevin R.; Tarca, Adi L.; Gomez-Lopez, Nardhy
    Objective To comprehensively characterize monocyte and neutrophil responses to E. coli and its product [lipopolysaccharide (LPS) or endotoxin] in vitro during pregnancy.