15-Hydroxyprostaglandin Dehydrogenase and Cyclooxygenase 2 Messenger Ribonucleic Acid Expression and Immunohistochemical Localization in Human Cervical Tissue during Term and Preterm Labor

Törnblom, Susanne Abelin; Patel, Falguni A.; Byström, Birgitta; Giannoulias, D.; Malmström, Anders; Sennström, Maria; Lye, Stephen J.; Challis, John; Ekman, Gunvor

doi:10.1210/jc.2003-031149

Cited by 32 publications

(21 citation statements)

References 46 publications

(54 reference statements)

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“…COX-2 inhibitors inhibit preterm labor (11,12). In contrast to COX-2, 15-PGDH levels are decreased in the ripe cervix at term relative to the high levels of this enzyme before cervical ripening (6). Together, these studies indicate that COX-2 and 15-PGDH are inversely correlated in the human cervix, thereby regulating the relative abundance of cervical PGE 2 and cervical ripening.…”

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confidence: 87%

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Prostaglandin dehydrogenase is a target for successful induction of cervical ripening

Kishore

Liang

Kanchwala

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The cervix represents a formidable structural barrier for successful induction of labor. Approximately 10% of pregnancies undergo induction of cervical ripening and labor with prostaglandin (PG) E 2 or PGE analogs, often requiring many hours of hospitalization and monitoring. On the other hand, preterm cervical ripening in the second trimester predicts preterm birth. The regulatory mechanisms of this paradoxical function of the cervix are unknown. Here, we show that PGE 2 uses cell-specific EP2 receptor-mediated increases in Ca 2+ to dephosphorylate and translocate histone deacetylase 4 (HDAC4) to the nucleus for repression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH). The crucial role of 15-PGDH in cervical ripening was confirmed in vivo. Although PGE 2 or 15-PGDH inhibitor alone did not alter gestational length, treatment with 15-PGDH inhibitor + PGE 2 or metabolism-resistant dimethyl-PGE 2 resulted in preterm cervical ripening and delivery in mice. The ability of PGE 2 to selectively autoamplify its own synthesis in stromal cells by signaling transcriptional repression of 15-PGDH elucidates long sought-after molecular mechanisms that govern PG action in the cervix. This report details unique mechanisms of action in the cervix and serves as a catalyst for (i) the use of 15-PGDH inhibitors to initiate or amplify low-dose PGE 2 -mediated cervical ripening or (ii) EP2 receptor antagonists, HDAC4 inhibitors, and 15-PGDH activators to prevent preterm cervical ripening and preterm birth.espite decades of clinical use for cervical ripening and induction of labor, mechanisms of prostaglandin (PG)-mediated cervical ripening are largely unknown. Likewise, it is not understood why some women at term respond to vaginal PGs for cervical ripening whereas others do not. Although failure rates vary depending on preparation, method of administration, definition of failure, dose, and dosing interval, in general the overall risk of the cervix remaining unchanged or unfavorable for induction of labor 12-24 h after vaginal PGs is 21.6% (1), which is consistent with a recent report in which 122 of 488 (25%) women failed to obtain a ripe cervix (as defined by Bishop Score < 7) after 4 PGE 2 (3 mg) tablets (2). Further, PGE 2 treatment leads to uterine hyperstimulation in 1-5.8%, of which 31% are associated with abnormalities in fetal heart rhythm (3). Both problems require emergency treatment and, in many cases, urgent operative delivery.Increased endogenous cervical PGs are derived from increased expression of the enzyme cyclooxygenase-2 (COX-2), which converts arachidonic acid to PGH 2 , which is then converted by PGE synthase (PTGES) to PGE 2 . Increases in cervical PGE 2 are prevented not only by low levels of COX-2 but also by high levels of the enzyme 15-prostaglandin dehydrogenase (15-PGDH) that inactivates PGE 2 by converting it to inactive 15-keto-PGE 2 (4-6). Hence, tissue levels of PGE 2 are regulated by the relative abundance of COX-2 and 15-PGDH enzymes. COX-2 levels increase in the cervix at term and in the myom...

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confidence: 87%

“…Increases in cervical PGE 2 are prevented not only by low levels of COX-2 but also by high levels of the enzyme 15-prostaglandin dehydrogenase (15-PGDH) that inactivates PGE 2 by converting it to inactive 15-keto-PGE 2 (4)(5)(6). Hence, tissue levels of PGE 2 are regulated by the relative abundance of COX-2 and 15-PGDH enzymes.…”

mentioning

confidence: 99%

Prostaglandin dehydrogenase is a target for successful induction of cervical ripening

Kishore

Liang

Kanchwala

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Importantly, the likelihood both of preterm delivery and of poor neonatal outcome is greater in the presence of intrauterine inflammation (Shim et al 2004). Fewer studies have examined cervical and myometrial tissues from women in preterm labour, although those that have suggested that inflammatory processes operate here also (Tornblom et al 2004, Osman et al 2006.…”

Section: Complicated Labourmentioning

confidence: 99%

Inflammatory pathways in female reproductive health and disease

Jabbour¹,

Sales²,

Catalano³

et al. 2009

Reproduction

294

226

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Inflammation involves alterations to vascular and immune cell function. It is well recognised that many physiological reproductive events such as ovulation, menstruation, implantation and onset of labour display hallmark signs of inflammation. These are orchestrated by specific molecular pathways involving a host of growth factors, cytokines, chemokines and lipid mediators. Resumption of normal reproductive function involves prompt and proper resolution of these inflammatory pathways. Recent literature confirms that resolution of inflammatory pathways involves specific biochemical events that are activated to re-establish homeostasis in the affected tissue. Moreover, initiation and maintenance of inflammatory pathways are the key components of many pathologies of the reproductive tract and elsewhere in the body. The onset of reproductive disorders or disease may be the result of exacerbated activation and maintenance of inflammatory pathways or their dysregulated resolution. This review will address the role of inflammatory events in normal reproductive function and its pathologies.

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“…premature cervical dilation in the midtrimester) pregnancies. 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].…”

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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15-Hydroxyprostaglandin Dehydrogenase and Cyclooxygenase 2 Messenger Ribonucleic Acid Expression and Immunohistochemical Localization in Human Cervical Tissue during Term and Preterm Labor

Cited by 32 publications

References 46 publications

Prostaglandin dehydrogenase is a target for successful induction of cervical ripening

Prostaglandin dehydrogenase is a target for successful induction of cervical ripening

Inflammatory pathways in female reproductive health and disease

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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