Medroxyprogesterone Acetate Modulates Remodeling, Immune Cell Census, and Nerve Fibers in the Cervix of a Mouse Model for Inflammation-induced Preterm Birth

Yellon, Steven M.; Ebner, Charlotte A.; Elovitz, Michal A.

doi:10.1177/1933719108325757

Cited by 47 publications

(37 citation statements)

References 42 publications

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“…As previously reported, this model results in a high rate of PTB within 24 h, and does not result in maternal mortality [8][9][10][11][12]. In addition, this model is associated with preterm cervical ripening, as previously demonstrated [9,13,14]. In this model, cervical ripening is noted by an increase in cytokines, an influx of polymorphonuclear leukocytes, as well as histological evidence with increase in mucin and breakdown of cervical stroma.…”

Section: Mouse Models Of Ptbsupporting

confidence: 69%

Preterm and Term Cervical Ripening in CD1 Mice (Mus musculus): Similar or Divergent Molecular Mechanisms?1

González

Chai

et al. 2009

Biology of Reproduction

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Premature cervical ripening is believed to contribute to preterm birth (PTB). Preterm cervical ripening may be due to an aberrant regulation in timing of the same processes that occur at term, or may result from unique molecular mechanisms. Using mouse models of PTB, this study sought to investigate if the molecular mechanisms that govern cervical ripening were similar between preterm and term. Lipopolysaccharide (LPS) is infused into the uterine horn to create a mouse model of inflammation-induced PTB. For a noninfectious model of PTB, RU486 was administered. Both models result in delivery of pups in 8-24 h. Cervical tissues were collected from these models, as well as throughout gestation. Cervical tissues from E15 (preterm), E15 LPS (preterm inflammation), and E18.5 (term) were used for microarray analysis (n = 18). Additional experiments using gestational time course specimens were performed to confirm microarray results. Specific gene pathways were differentially expressed between the groups. Genes involved in immunity and inflammation were increased in the cervix in inflammation-induced PTB; term labor was not associated with differential expression of immune pathways. Cytokine expression was not increased in cervices during term labor, but was increased in the pospartum period. Epithelial cell differentiation pathway was significantly altered in term, but not preterm, labor. Activation of immune pathways may be sufficient for cervical ripening, but does not appear necessary. Differential expression of the epithelial cell differentiation pathway appears necessary in the process of cervical repair. Our results indicate that the molecular mechanisms governing preterm and term cervical ripening are distinctly different.

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Section: Mouse Models Of Ptbsupporting

confidence: 69%

Preterm and Term Cervical Ripening in CD1 Mice (Mus musculus): Similar or Divergent Molecular Mechanisms?1

González

Chai

et al. 2009

Biology of Reproduction

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“…However, in the cervix of prepartum PGR-BKO mice, collagenolytic processes that remodel the extracellular matrix of the cervix in preparation for birth were not affected by the lack of recruitment of neutrophils. These findings do not exclude the possibility that activation of a limited number of resident immune cells may drive increased production of prostaglandins, proinflammatory cytokines, and collagen degradation in the prepartum cervix at term [25,43,44] or are important for inflammation-induced preterm cervical remodeling [29,45]. Based upon the present findings in PGR-BKO mice, the PGR-B isoform is unlikely to be involved in such activational cascades that overcome the progestational protection of peak progesterone in circulation.…”

Section: Discussioncontrasting

confidence: 55%

“…Nonpregnant (NP) mice in estrus or metestrus, based upon assessment of vaginal smears, served as additional controls. The cervix was removed, postfixed overnight, embedded in paraffin, sectioned (thickness, 10 lm), and processed as previously detailed [28,29]. Briefly, sections of cervix from each mouse were stained with picrosirius red to identify collagen and cross-link structure.…”

Section: Cervical Processing and Analysismentioning

confidence: 99%

“…Other sections were processed by immunohistochemistry to stain macrophages (BM8 antibody, 1:800; Bachem Americas, Inc.) or neutrophils (7/4 antibody, 1:100; AbD Serotec), then counterstained with hematoxylin to identify cell nuclei. As previously discussed [29], these antibodies are widely used and specific for differentiated immune cells. Cross-reactivity of the 7/4 antisera with naïve monocytes is lost with differentiation into macrophages as cells migrate into tissue.…”

Section: Cervical Processing and Analysismentioning

confidence: 99%

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Remodeling of the Cervix and Parturition in Mice Lacking the Progesterone Receptor B Isoform

Yellon

Oshiro

Chhaya

et al. 2011

Biology of Reproduction

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Withdrawal of progestational support for pregnancy is part of the final common pathways for parturition, but the role of nuclear progesterone receptor (PGR) isoforms in this process is not known. To determine if the PGR-B isoform participates in cervical remodeling at term, cervices were obtained from mice lacking PGR-B (PGR-BKO) and from wild-type (WT) controls before or after birth. PGR-BKO mice gave birth to viable pups at the same time as WT controls during the early morning of Day 19 postbreeding. Morphological analyses indicated that by the day before birth, cervices from PGR-BKO and WT mice had increased in size, with fewer cell nuclei/area as well as diminished collagen content and structure, as evidenced by optical density of picrosirius red-stained sections, compared to cervices from nonpregnant mice. Moreover, increased numbers of resident macrophages, but not neutrophils, were found in the prepartum cervix of PGR-BKO compared to nonpregnant mice, parallel to findings in WT mice. These results suggest that PGR-B does not contribute to the growth or degradation of the extracellular matrix or proinflammatory processes associated with recruitment of macrophages in the cervix leading up to birth. Rather, other receptors may contribute to the progesterone-dependent mechanism that promotes remodeling of the cervix during pregnancy and in the proinflammatory process associated with ripening before parturition.

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“…Human cervical biopsy specimens have been obtained from patients in preterm and term labor, preterm and term nonlabor and nonpregnant patients after a hysterectomy to describe the cervical extracellular matrix and its relationship to abnormal labor [2][3][4][5][6][7][8][9][10][11][12][13]15,16,18,25,28,[46][47][48]. Animal studies have also provided insight into the changes in extracellular matrix that occur in the uterine cervix during pregnancy [17,[19][20][21][22]28,33,34,36,[49][50][51][52][53][54]. Studies of cervical biopsy tissue have been conducted in pregnant women as early as 1960 [18].…”

Section: Importance Of the Studymentioning

confidence: 99%

The transcriptome of cervical ripening in human pregnancy before the onset of labor at term: Identification of novel molecular functions involved in this process

Hassan¹,

Romero²,

Tarca³

et al. 2009

The Journal of Maternal-Fetal & Neonatal Medicine

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Objective. The aim of this study was to identify changes in the cervical transcriptome in the human uterine cervix as a function of ripening before the onset of labor. Study Design. Human cervical tissue was obtained from women at term not in labor with ripe (n ¼ 11) and unripe (n ¼ 11) cervices and profiled using Affymetrix GeneChip 1 HGU133Plus2.0 arrays. Gene expression was analyzed using a moderated t-test (False Discovery Rate 5%). Gene ontology and pathway analysis were performed. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for confirmation of selected differentially expressed genes. Results.(1) Ninety-one genes were differentially expressed between ripe and unripe groups. (2) Cervical ripening was associated with enrichment of specific biological processes (e.g. cell adhesion, regulation of anatomical structure), pathways and 11 molecular functions (e.g. extracelluar matrix (ECM)-structural constituent, protein binding, glycosaminoglycan binding). (3) qRT-PCR confirmed that 9 of 11 tested differentially expressed genes (determined by microarray) were upregulated in a ripe cervix (e.g. MYOCD, VCAN, THBS1, COL5A1). (4) Twenty-three additional genes related to ECM metabolism and adhesion molecules were differentially regulated (by qRT-PCR) in ripe cervices. Conclusion.(1) This is the first description of the changes in the human cervical transcriptome with ripening before the onset of labor. (2) Biological processes, pathways and molecular functions were identified with the use of this unbiased approach. (3) In contrast to cervical dilation after term labor, inflammation-related genes did not emerge as differentially regulated with cervical ripening. (4) Myocardin was identified as a novel gene upregulated in human cervical ripening.

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Medroxyprogesterone Acetate Modulates Remodeling, Immune Cell Census, and Nerve Fibers in the Cervix of a Mouse Model for Inflammation-induced Preterm Birth

Cited by 47 publications

References 42 publications

Preterm and Term Cervical Ripening in CD1 Mice (Mus musculus): Similar or Divergent Molecular Mechanisms?1

Preterm and Term Cervical Ripening in CD1 Mice (Mus musculus): Similar or Divergent Molecular Mechanisms?1

Remodeling of the Cervix and Parturition in Mice Lacking the Progesterone Receptor B Isoform

The transcriptome of cervical ripening in human pregnancy before the onset of labor at term: Identification of novel molecular functions involved in this process

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