Papers by Elizabeth Bonney
Journal of The Society for Gynecologic Investigation, 1998
Reproductive Sciences, Jan 7, 2021
Epidemiological evidence suggests that normal pregnancy in women is associated with decreased car... more Epidemiological evidence suggests that normal pregnancy in women is associated with decreased cardiovascular risk in later life. Clinical studies have provided evidence that alterations in vascular function and structure are detectable long after delivery. To understand these findings, we examined mesenteric artery reactivity at both early (3 days and 2-4 weeks) and late (12 weeks) postpartum (PP) time points in relation to late pregnancy (LP) and lactation. Vessels from virgin controls, LP, PP, and nursing and non-nursing mothers were tested for responses to phenylephrine (PE), high potassium solutions (high K +), and acetylcholine (ACh). Passive arterial distensibility, vessel dimensions, and collagen and elastin content were evaluated for the studied groups. We observed that (1) there was a significant inhibition of vascular reactivity to PE in LP, 3 days and 2 weeks PP vessels that returned to pre-pregnancy levels at 4 and 12 weeks PP; (2) inhibition of NO production in PP vessels restored PE-induced constriction to prepregnancy levels; (3) vasodilator responses to ACh were similar at all PP periods; (4) LP and early PP was associated with a persistent increase in arterial distensibility that correlates with a PP-induced reduction in wall collagen, and regressed to preconception levels at 12 weeks PP; (5) vessels from non-nursing PP mice demonstrated an increased PE reactivity, diminished responses to ACh, and reduced distensibility compared to breastfeeding mice. These studies provide a timeframe for mesenteric artery adaptations that occur during pregnancy and extend to the PP period, but which may be modified by PP events.
American Journal of Perinatology
Objective This study evaluated the effect of pregnancy on the pulmonary innate immune response in... more Objective This study evaluated the effect of pregnancy on the pulmonary innate immune response in a mouse model of acute lung injury (ALI) using nebulized lipopolysaccharide (LPS). Study Design Pregnant (day 14) C57BL/6NCRL mice and nonpregnant controls received nebulized LPS for 15 minutes. Twenty-four hours later, mice were euthanized for tissue harvest. Analysis included blood and bronchoalveolar lavage fluid (BALF) differential cell counts, whole-lung inflammatory cytokine transcription levels by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), and whole-lung vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and BALF albumin by western blot. Mature bone marrow neutrophils from uninjured pregnant and nonpregnant mice were examined for chemotactic response using a Boyden chamber and for cytokine response to LPS by RT-qPCR. Results In LPS-induced ALI, pregnant mice had higher BALF total cell (p < 0.001) and n...
Frontiers in Physiology
The risk of postpartum (PP) stroke is increased in complicated pregnancies. Deficiency in CD4 T c... more The risk of postpartum (PP) stroke is increased in complicated pregnancies. Deficiency in CD4 T cell subsets is associated with preeclampsia and may contribute to PP vascular disease, including internal carotid artery (ICA) stenosis and stroke. We hypothesized that CD4 T cell deficiency in pregnancy would result in ICA dysregulation, including enhanced ICA vasoconstriction. We characterized the function, mechanical behavior, and structure of ICAs from C57BL/6 (WT) and CD4 deficient (CD4KO) mice, and assessed the role of NO in the control of ICA function at pre-conception and PP. WT and CD4KO mice were housed under pathogen-free conditions, mated to same-strain males, and allowed to litter or left virgin. At 3 days or 4 weeks PP, mice were euthanized. The responses to phenylephrine (PE), high K+ and acetylcholine (ACh) were assessed in pressurized ICAs before and after NOS inhibition. Passive lumen diameters were measured at 3–140 mmHg. eNOS and iNOS expression as well as the presenc...
Placenta and Reproductive Medicine
Galveston, Texas, USA, a group of young investigators convened. They gathered and voiced concern ... more Galveston, Texas, USA, a group of young investigators convened. They gathered and voiced concern that there is critical need for a platform whereby young research scientists and clinicians can present their research progress and significant achievements. Following this initial gathering, a virtual symposium, hosted by the PREBIC Australasia Branch was dedicated to the Youth Forum on
Frontiers in Virology
Pregnant mice infected with Lymphocytic Choriomeningitis Virus (Armstrong) (LCMV-Arm) experience ... more Pregnant mice infected with Lymphocytic Choriomeningitis Virus (Armstrong) (LCMV-Arm) experience high viral loads in the placenta and uterine tissue by 5–8 days post-infection, a time when the virus is nearly completely cleared from the spleen and blood. Interleukin 10 (IL-10) plays a crucial role in T cell responses associated with systemic viral clearance. Using the LCMV-arm model of infection, we examined first, whether IL-10 is involved in viral clearance in the placenta and uterine tissue and secondly, the potential mechanisms underlying this phenomenon. C57BL/6 (WT) and mice deficient in IL-10 (IL-10 KO) were infected with LCMV-Arm on day 10 of pregnancy. Placenta and uterine tissue, collected 2 and 8 days later, were analyzed using real time RT-PCR, plaque assays for viral load, and flow cytometry. In WT mice placenta and uterine tissue expression of IL-10 was elevated with LCMV-Arm infection. Fetus resorption was elevated in WT on days 2 and 8 post-infection as compared to I...
PLOS ONE, 2021
Background Microbial invasion of the intraamniotic cavity and intraamniotic inflammation are fact... more Background Microbial invasion of the intraamniotic cavity and intraamniotic inflammation are factors associated with spontaneous preterm birth. Understanding the route and kinetics of infection, sites of colonization, and mechanisms of host inflammatory response is critical to reducing preterm birth risk. Objectives This study developed an animal model of ascending infection and preterm birth with live bacteria (E. coli) in pregnant CD-1 mice with the goal of better understanding the process of microbial invasion of the intraamniotic cavity and intraamniotic inflammation. Study design Multiple experiments were conducted in this study. To determine the dose of E. coli required to induce preterm birth, CD-1 mice were injected vaginally with four different doses of E. coli (103, 106, 1010, or 1011 colony forming units [CFU]) in 40 μL of nutrient broth or broth alone (control) on an embryonic day (E)15. Preterm birth (defined as delivery before E18.5) was monitored using live video. E. ...
Frontiers in Physiology, 2020
Objective: Protection of the fetus within the amniotic sac is primarily attained by remodeling fe... more Objective: Protection of the fetus within the amniotic sac is primarily attained by remodeling fetal membrane (amniochorion) cells through cyclic epithelial to mesenchymal and mesenchymal to epithelial (EMT and MET) transitions. Endocrine and paracrine factors regulate EMT and MET during pregnancy. At term, increased oxidative stress forces a terminal state of EMT and inflammation, predisposing to membrane weakening and rupture. IL-6 is a constitutively expressed cytokine during gestation, but it is elevated in term and preterm births. Therefore, we tested the hypothesis that IL-6 can determine the fate of amnion membrane cells and that pathologic levels of IL-6 can cause a terminal state of EMT and inflammation, leading to adverse pregnancy outcomes. Methods: Primary amnion epithelial cells (AECs) were treated with recombinant IL-6 (330, 1,650, 3,330, and 16,000 pg/ml) for 48 h (N = 5). IL-6-induced cell senescence (aging), cell death (apoptosis and necrosis), and cell cycle changes were studied using flow cytometry. Cellular transitions were determined by immunocytochemistry and western blot analysis, while IL-6 signaling (activation of signaling kinases) was measured by immunoassay. Inflammatory marker matrix metalloproteinase (MMP9) and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations were measured using a Fluorokine E assay and ELISA, respectively. Amniotic membranes collected on gestational day (D) 12 and D18 from IL-6 knockout (KO) and control C57BL/6 mice (N = 3 each) were used to determine the impact of IL-6 on cell transitions. Fold changes were measured based on the mean of each group. Results: IL-6 treatment of AECs at physiologic or pathologic doses increased JNK and p38MAPK activation; however, the activation of signals did not cause changes in AEC cell cycle, cellular senescence, apoptosis, necrosis, cellular transitions, or inflammation (MMP9 and GM-CSF) compared to control. EMT markers were higher on D18 compared to D12 regardless of IL-6 status in the mouse amniotic sac.
Placenta, 2019
The role of the immune system in term (TL) and preterm labor (PTL) is unknown. Despite the fact t... more The role of the immune system in term (TL) and preterm labor (PTL) is unknown. Despite the fact that globally, PTL remains the most important cause of childhood mortality. Infection, typically of the fetal membranes, termed chorioamnionitis, is the best-understood driver of PTL, but the mechanisms underpinning other causes, including idiopathic and stretch-induced PTL, are unclear, but may well involve activation of the maternal immune system. The final common pathway of placental dysfunction, fetal membrane rupture, cervical dilation and uterine contractions are highly complex processes. At term, choriodecidual rather than myometrial inflammation is thought to drive the onset of labor and similar findings are present in different types of PTL including idiopathic PTL. Although accumulated data has confirmed an association between the immune response and preterm birth, there is yet a need to understand if this response is an initiator or a consequence of tissue-level dysregulation. This review focuses on the potential role of macrophages and T cells in innate and adaptive immunity relevant to preterm birth in humans and animal models.
American Journal of Obstetrics and Gynecology, 2014
The practice of medicine continues to evolve, and individual circumstances will vary. This public... more The practice of medicine continues to evolve, and individual circumstances will vary. This publication reflects information available at the time of its submission for publication and is neither designed nor intended to establish an exclusive standard of perinatal care. This publication is not expected to reflect the opinions of all members of the Society for Maternal-Fetal Medicine. Heath care measurement and evaluation is an integral piece of the health care system. The creation and assessment of care performance metrics are important and relevant for the obstetric community including both clinicians and patients. Careful deliberation is required to create a measurement system that results in optimal care for women and families. This article reviews the current approaches to measuring quality in obstetrics.
Obstetrics and Gynecology Clinics of North America, 2016
The maternal immune system is complex and governed by multiple hormonal and metabolic factors, in... more The maternal immune system is complex and governed by multiple hormonal and metabolic factors, including those provided to her via the fetus. Understanding of the balance between maternal tolerance and protection of the fetus may require thinking from multiple theoretical approaches to general problem of immune activation and tolerance. The basics for this process are discussed here and may suggest both specific experiments in human and animal models and specific interventions in pregnant patients with immune system-related disease.
American Journal of Reproductive Immunology
To generate new hypotheses, sometimes a "systems" approach is needed. In this review, I focus on ... more To generate new hypotheses, sometimes a "systems" approach is needed. In this review, I focus on the mitogen-activated kinase p38 because it has been recently shown to play an important role in the developmental programing and senescence of normal and stressed reproductive tissues. What follows is an overview of (i) pathways of p38 activation and their involvement in basic biological processes, (ii) evidence that p38 is involved in the homeostasis of reproductive tissues, (iii) how focus on p38 can be incorporated into investigation of normal and stressed pregnancies. Existence of excellent reviews will be mentioned as well as relevant animal models. K E Y W O R D S immunology, MAPK14 p38 pregnancy, reproduction How to cite this article: Bonney EA. Mapping out p38MAPK.
International Journal of Molecular Sciences
Multinucleate syncytialized trophoblast is found in three forms in the human placenta. In the ear... more Multinucleate syncytialized trophoblast is found in three forms in the human placenta. In the earliest stages of pregnancy, it is seen at the invasive leading edge of the implanting embryo and has been called primitive trophoblast. In later pregnancy, it is represented by the immense, multinucleated layer covering the surface of placental villi and by the trophoblast giant cells found deep within the uterine decidua and myometrium. These syncytia interact with local and/or systemic maternal immune effector cells in a fine balance that allows for invasion and persistence of allogeneic cells in a mother who must retain immunocompetence for 40 weeks of pregnancy. Maternal immune interactions with syncytialized trophoblast require tightly regulated mechanisms that may differ depending on the location of fetal cells and their invasiveness, the nature of the surrounding immune effector cells and the gestational age of the pregnancy. Some specifically reflect the unique mechanisms involved...
American Journal of Reproductive Immunology
Biology of Reproduction
OBJECTIVE Oxidative stress (OS) induced stress signaler p38 mitogen-activated protein kinase (p38... more OBJECTIVE Oxidative stress (OS) induced stress signaler p38 mitogen-activated protein kinase (p38MAPK) activation and fetal membrane senescence are associated with parturition. This study determined changes in Glycogen synthase kinase3β (GSK3β) and its regulation by p38MAPK in effecting senescence to further delineate the molecular mechanism involved in senescence. METHODS Primary human amnion epithelial cells (AECs) and amnion mesenchymal cells (AMCs) were treated with cigarette smoke extract (CSE, OS inducer). Expression of total and phosphorylated GSK3β and p38MAPK, and that of GSK3β’s downstream targets: β-catenin and Nuclear factor erythroid 2–related factor 2 (Nrf2) (western blot analysis), cell cycle regulation and senescence (flow cytometry) were determined. The specificity of GSK3β and p38MAPK’s mechanistic role was tested by co-treating cells with their respective inhibitors, CHIR99021 and SB203580. Exosomal secretion of β-catenin from OS-induced cells was confirmed by imm...
Biomedical Reports
Adiponectin levels are associated with anti-Müllerian hormone (AMH) and kisspeptin levels in non-... more Adiponectin levels are associated with anti-Müllerian hormone (AMH) and kisspeptin levels in non-ovarian tissues. The objective of the present study was to investigate the association between adiponectin and the genes important for ovarian follicular development and ovarian reserve, specifically AMH and kisspeptin, and their corresponding receptors. In the first experiment, the mRNA levels of anti-Müllerian hormone (amh) and its receptor (Amhr2), as well as those of kisspeptin (Kiss1) and its receptor (Kiss1r), were quantified by reverse transcription-polymerase chain reaction analysis in the ovaries of two groups of mice [adiponectin-knockout (KO) vs. control] that underwent oophorectomy. The second experiment measured follicular phase serum AMH and follicular fluid adiponectin levels in 25 women who underwent controlled ovarian hyperstimulation for in vitro fertilization. Compared with the control mice, adiponectin-KO mice had 6.5 times lower Kiss1 mRNA levels (P= 0.009) and a tendency for lower ovarian Kiss1r mRNA expression levels (P= 0.06). However, adiponectin-KO mice had significantly higher Amhr2 mRNA levels (P=0.01). In all women participants, there was a positive correlation between serum AMH and follicular fluid adiponectin concentrations (r=0.54, P=0.006). The findings of the present study indicate that adiponectin may play a role in ovarian physiology through its impact on genes crucial for ovarian follicular development and ovarian reserve, such as kisspeptin and AMH. Understanding the role of adiponectin in ovarian function may improve our knowledge of the pathophysiology underlying ovulatory dysfunction in obese women, who usually have low adiponectin levels, and overcome reproductive barriers.
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Papers by Elizabeth Bonney