Macrophage-induced reactive oxygen species promote myometrial contraction and labor-associated mechanisms† (original) (raw)
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Biology of Reproduction, 2012
Preterm delivery is the leading cause of perinatal mortality and morbidity. Current tocolytics target myometrial contractions, a late step in the labor cascade. Identifying earlier events in parturition may lead to more effective therapeutic strategies. We hypothesized that inflammatory events in decidua (the maternal-fetal interface), characterized by leucocyte infiltration, are an early event during term and preterm labor (PTL). Leucocyte abundance in decidua of human pregnancies was quantified following term labor and PTL (idiopathic and infection associated), in conjunction with investigation of temporal inflammatory events in rat uterus during the perilabor period and in PTL induced by mifepristone. In human decidua, macrophage numbers were 4-fold higher in term labor (P , 0.01) and 2.5-fold higher in non-infectionassociated PTL (P , 0.05) than in term nonlaboring samples. Neutrophil abundance was unchanged with labor but elevated in PTL with infection (5-to 53-fold increase; P , 0.01). T and NK cells were more abundant in idiopathic PTL than TL (P , 0.05). In rat, decidual macrophage infiltration increased 4.5fold 12 h prior to labor and remained elevated during labor and early postpartum (P , 0.01). Decidual infiltration preceded that of the myometrium and was 4-fold higher (P , 0.01). In rat PTL, decidual macrophage numbers were also elevated (P , 0.01) and exceeded those of the myometrium (P , 0.05). These studies show for the first time that leucocytes infiltrate decidua during labor at term and preterm, supporting a role for leucocyte-derived inflammatory mediators in decidual activation. In the rat, this occurred prior to labor, suggesting it is an early event during parturition and thus a potential target for intervention.
Biology of Reproduction, 2012
Preterm delivery is the leading cause of perinatal mortality and morbidity. Current tocolytics target myometrial contractions, a late step in the labor cascade. Identifying earlier events in parturition may lead to more effective therapeutic strategies. We hypothesized that inflammatory events in decidua (the maternal-fetal interface), characterized by leucocyte infiltration, are an early event during term and preterm labor (PTL). Leucocyte abundance in decidua of human pregnancies was quantified following term labor and PTL (idiopathic and infection associated), in conjunction with investigation of temporal inflammatory events in rat uterus during the perilabor period and in PTL induced by mifepristone. In human decidua, macrophage numbers were 4-fold higher in term labor (P , 0.01) and 2.5-fold higher in non-infectionassociated PTL (P , 0.05) than in term nonlaboring samples. Neutrophil abundance was unchanged with labor but elevated in PTL with infection (5-to 53-fold increase; P , 0.01). T and NK cells were more abundant in idiopathic PTL than TL (P , 0.05). In rat, decidual macrophage infiltration increased 4.5fold 12 h prior to labor and remained elevated during labor and early postpartum (P , 0.01). Decidual infiltration preceded that of the myometrium and was 4-fold higher (P , 0.01). In rat PTL, decidual macrophage numbers were also elevated (P , 0.01) and exceeded those of the myometrium (P , 0.05). These studies show for the first time that leucocytes infiltrate decidua during labor at term and preterm, supporting a role for leucocyte-derived inflammatory mediators in decidual activation. In the rat, this occurred prior to labor, suggesting it is an early event during parturition and thus a potential target for intervention. decidua, human reproduction, labor, leucocyte, macrophage, myometrium, parturition, preterm labor, reproductive immunology
A new role for monocytes in modulating myometrial inflammation during human labor
Biology of reproduction, 2014
Here we fully characterize the cytokine profile of laboring human myometrium using Luminex analysis of 48 cytokine proteins, and stereologically quantified infiltration of monocytes and neutrophils into the myometrium. We hypothesized that monocytes can regulate their accumulation in the myometrium by disruption of proinflammatory cytokines to prevent an uncontrolled inflammatory response after labor onset. We isolated primary human myometrial cells (HMCs) from term, nonlaboring myometrial biopsies. Confluent HMCs were cocultured directly with human monocytic (THP-1) or lymphocytic (U937) cells, and with the same cells spatially separated by a membrane insert. After 72 h, HMCs and THP-1 were harvested separately, and RNA was extracted and analyzed by quantitative PCR. Coculture supernatants were collected and analyzed by Luminex assay and ELISA. We found that the laboring human myometrium produces significantly higher amounts of interleukin (IL) 6, IL9, IL18, IL1RA, CCL2, CCL7, CXCL...
JCI Insight, 2021
and Human Services, under contract HHSN275201300006C. We thank the physicians and nurses from the Center for Advanced Obstetrical Care and Research and the Intrapartum Unit at Detroit Medical Center for help in collecting tissue samples. We thank Yi Xu and Jose Galaz for help analyzing flow cytometry and clinical data, Derek Miller for critical reading of the manuscript, and David Sharkey for performing the imulus amebocyte lysate assay. RR contributed as an employee of the US federal government. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Journal of Cellular and Molecular Medicine, 2013
This study aimed to determine the mechanism of uterine activation during labour, both term (TL) and preterm (PTL). We hypothesized that the peripheral leucocytes are recruited to uterine tissues by locally produced cytokines where they contribute to the initiation of parturition. Mouse uteri were collected (i) during gestation, TL and post-partum (PP), (ii) during PTL initiated by intrauterine infusion of LPS (125 lg) or (iii) injection of the progesterone receptor antagonist RU486 and analysed for multiple cytokine expression levels by real-time polymerase chain reaction (RT-PCR) and 23-plex Cytokine assay or enzymatically dispersed for assessment of immune cell populations. Markers of myeloid cell differentiation (Gr1, Neu7/4 and F4/80) were evaluated by FACS to define tissue macrophages (Macs), monocytes (M) and neutrophils (N) and by immunohistochemistry to detect tissue Macs and N. Our results indicate that: (1) Macs were elevated in mouse myometrium before TL (P < 0.05) followed by an increase in M and N; these changes were accompanied by an increase in multiple pro-inflammatory cytokines/chemokines genes. The expression of corresponding proteins increased PP. (2) TL and RU486-PTL models showed similar gene/protein expression profiles, (3) LPS-PTL was characterized by strong pro-inflammatory response and massive influx of N in myometrial tissues showing a pattern different from TL and RU486-PTL, (4) The PP period appears similar in all three models, with elevated myometrial cytokine levels and high infiltration of immune cells. We concluded that leucocytes infiltrate myometrium around the time of parturition implicating their potential role in labour activation (both term and preterm) and major role in PP uterine involution.
Laboratory Investigation, 2001
Impaired invasion of uteroplacental arteries by extravillous trophoblast cells is a key pathogenic mechanism of preeclampsia. We previously demonstrated that reduced trophoblast invasion into uteroplacental spiral arteries was associated with an excess of macrophages in and around these arteries. To explore the significance of these observations, we correlated the extent of extravillous trophoblast apoptosis in placental bed biopsy specimens with macrophage distribution and studied the effect of macrophages upon trophoblast apoptosis in vitro. Extravillous trophoblast hybrid cells were cocultured with activated macrophages exposed to exogenous tumor necrosis factor ␣ (TNF␣), anti-tumor necrosis factor receptor I (TNF-RI), and tryptophan depletion, and the rates of trophoblast apoptosis were measured. Extravillous trophoblast hybrid cells showed increased rates of apoptosis following exposure to exogenous TNF␣, with tryptophan depletion, and when cocultured with activated macrophages. The proapoptotic effects of macrophages in vitro were completely inhibited only by simultaneous addition of tryptophan and anti-TNF-RI. Our data indicate that macrophages, residing in excess in the placental bed of preeclamptic women, are able to limit extravillous trophoblast invasion of spiral arterial segments through apoptosis mediated by the combination of TNF␣ secretion and tryptophan depletion. The mechanisms by which macrophages are activated and recruited to the placental bed are presently unknown but are likely central to the pathogenesis of preeclampsia. (Lab Invest 2001,
BMC pregnancy and childbirth, 2013
The development of the in vitro cell culture model has greatly facilitated the ability to study gene expression and regulation within human tissues. Within the human uterus, the upper (fundal) segment and the lower segment may provide distinct functions throughout pregnancy and during labour. We have established primary cultured human myometrial cells, isolated from both upper and lower segment regions of the pregnant human uterus, and validated them for the purpose of studying human pregnancy and labour. The specific objectives of this study were to monitor the viability and characterize the expression profile using selected cellular, contractile and pregnancy associated markers in the primary cultured human myometrial cells. Labour has been described as an inflammatory process; therefore, the ability of these cells to respond to an inflammatory stimulus was also investigated. Myometrial cells isolated from paired upper segment (US) and lower segment (LS) biopsies, obtained from wo...