Inflammation of the Fetal Ovine Skin Following in utero Exposure to Ureaplasma parvum

School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
Reproductive sciences (Thousand Oaks, Calif.) (Impact Factor: 2.23). 11/2011; 18(11):1128-37. DOI: 10.1177/1933719111408114
Source: PubMed


There is increasing evidence linking in utero infection and inflammation to preterm birth. Many commensal urogenital tract microorganisms, including the Mycoplasmas and Ureaplasmas, are commonly detected in association with preterm birth. Using an ovine model of sterile fetal inflammation, we demonstrated previously that the fetal skin generates a robust inflammatory response following in utero exposure to lipopolysaccharides from Escherichia coli. The fetal skin's response to colonization of the amniotic fluid by viable microorganisms remains unstudied. We hypothesised that in utero infection with Ureaplasma parvum serovar 3 would induce a proinflammatory response in the fetal skin. We found that (1) cultured fetal keratinocytes (the primary cellular constituent of the epidermis) respond to U. parvum exposure in vitro by increasing the expression of the chemotactant monocyte chemoattractant protein 1 (MCP-1) but not interleukin 1β (IL-1β), IL-6, IL-8, or tumor necrosis factor-α (TNF-α); (2) the fetal skin's response to 7 days of U. parvum exposure is characterized by elevated expression of MCP-1, TNF-α, and IL-10; and (3) the magnitude of inflammatory cytokine/chemokine expression in the fetal skin is dependent on the duration of U parvum exposure. These novel findings provide further support for the role of the fetal skin in the development of fetal inflammation and the preterm birth that may follow.

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Available from: Christine L. Knox, Oct 04, 2015
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    • "Both U. urealyticum and U. parvum have been identified in amniotic fluid [9], [10], [11], [12], [13], fetal cord blood [14], fetal and neonatal lung [15], [16], cerebrospinal fluid [8], [17], and fetal gastro-intestinal aspirates [18], [19]. Various studies with animal models have demonstrated a causal relationship between monotypic intrauterine infection with Ureaplasma species and spontaneous preterm delivery [20], neonatal bronchopulmonary disease [21], [22], [23], [24], [25], antenatal brain injury [26], and fetal dermatitis [27]. However, the pathogenesis of ureaplasmal induced chorioamnionitis and adverse pregnancy outcome is not yet clearly elucidated. "
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    ABSTRACT: Ureaplasma parvum, an opportunistic pathogen of the human urogenital tract, has been implicated in contributing to chorioamnionitis, fetal morbidity, and fetal mortality. It has been proposed that the host genetic background is a critical factor in adverse pregnancy outcome as sequela to U. parvum intra-amniotic infection. To test this hypothesis we assessed the impact of intrauterine U. parvum infection in the prototypical TH1/M1 C57BL/6 and TH2/M2 BALB/c mouse strain. Sterile medium or U. parvum was inoculated into each uterine horn and animals were evaluated for intra-amniotic infection, fetal infection, chorioamnionitis and fetal pathology at 72 hours post-inoculation. Disease outcome was assessed by microbial culture, in situ detection of U. parvum in fetal and utero-placental tissues, grading of chorioamnionitis, and placental gene expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9. Placental infection and colonization rates were equivalent in both strains. The in situ distribution of U. parvum in placental tissues was also similar. However, a significantly greater proportion of BALB/c fetuses were infected (P<0.02). C57BL/6 infected animals predominantly exhibited mild to moderate chorioamnionitis (P<0.0001), and a significant reduction in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 compared to sham controls (P<0.02). Conversely, severe protracted chorioamnionitis with cellular necrosis was the predominant lesion phenotype in BALB/c mice, which also exhibited a significant increase in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 (P<0.01). Fetal pathology in BALB/c was multi-organ and included brain, lung, heart, liver, and intestine, whereas fetal pathology in C57BL/6 was only detected in the liver and intestines. These results confirm that the host genetic background is a major determinant in ureaplasmal induced chorioamnionitis with fetal infection and fetal inflammatory response.
    PLoS ONE 08/2012; 7(8):e44047. DOI:10.1371/journal.pone.0044047 · 3.23 Impact Factor
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    ABSTRACT: Preterm birth is associated with in utero infection and inflammation. Although the fetal membranes and fetus contribute to the intra-amniotic inflammatory profile, the relationships between a proinflammatory exposure to the fetal compartment and cytokine expression in the fetal skin are unknown. Using an ovine model, we asked whether the fetal skin would generate an extended response to inflammatory stimuli. Relative to control, intra-amniotic lipopolysaccharide (LPS) induced significant increases in cytokine/chemokine (interleukin 1β, IL-8, tumor necrosis factor-α, and monocyte chemoattractant protein 1) expression in skin that lasted for at least 15 days. Histological analysis demonstrated inflammatory cell infiltration in skin between 2 days and 15 days post-LPS exposure. In contrast to the fetal lung, the fetal skin continues to express proinflammatory cytokines for at least 15 days after exposure to LPS. These novel data suggest that the fetal skin may cause prolonged in utero inflammatory response causally associated with preterm birth.
    Reproductive sciences (Thousand Oaks, Calif.) 05/2012; 19(11):1181-9. DOI:10.1177/1933719112446079 · 2.23 Impact Factor
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    ABSTRACT: Abstract Objective: Inflammation is a mechanism of host response to infection which can be harmful when inappropriately modulated. Soluble ST2 (sST2) is a decoy receptor of interleukin (IL)-33, and this complex modulates the balance in the Th1/Th2 immune response. Moreover, sST2 inhibits the production of pro-inflammatory cytokines in cooperation with an anti-inflammatory cytokine, IL-10. The objectives of this study were to: 1) determine whether umbilical cord plasma sST2 concentration differ comparing preterm neonates with and without funisitis and/or the fetal inflammatory response syndrome (FIRS); and 2) evaluate the relationship between sST2 and IL-10 among neonates with funisitis and/or FIRS. Methods: Umbilical cord plasma was collected from neonates delivered prematurely due to preterm labor or preterm prelabor rupture of membranes with (n=36), and without funisitis (n=30). FIRS (umbilical cord IL-6 concentration ≥17.5 pg/mL) was identified in 29 neonates. Plasma sST2 and IL-10 concentrations were determined by ELISA. Results: The median umbilical cord plasma sST2 concentration was 6.7-fold higher in neonates with FIRS than in those without FIRS (median 44.6 ng/mL, interquartile range [IQR] 13.8-80.3 ng/mL vs. median 6.7 ng/mL, IQR 5.6-20.1 ng/mL; p<0.0001). Similarly, the median umbilical cord plasma sST2 concentration was 2.6-fold higher in neonates with funisitis than in those without funisitis (median 19.1 ng/mL; IQR 7.1-75.0 ng/mL vs. median 7.2 ng/mL; IQR 5.9-23.1 ng/mL; p=0.008). There was a strong positive correlation between sST2 and IL-10 in neonates with funisitis and/or FIRS (Spearman's Rho=0.7, p<0.0001). Conclusions: FIRS and funisitis are associated with an elevation of umbilical cord plasma concentrations of soluble ST2. This protein may participate in the fetal inflammatory response syndrome by promoting an anti-inflammatory effect in association with IL-10.
    The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 03/2013; 26(14). DOI:10.3109/14767058.2013.784258 · 1.37 Impact Factor
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