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- Dubicke, Aurelija, et al.
(författare)
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High-mobility group box protein 1 and its signalling receptors in human preterm and term cervix
- 2010
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Ingår i: Journal of Reproductive Immunology. - : Elsevier BV. - 1872-7603 .- 0165-0378. ; 84:1, s. 86-94
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to identify possible changes in mRNA and protein expression of high-mobility group box protein 1 (HMGB1) and its suggested receptors - receptor for advanced glycation end-products (RAGE) and Toll-like receptor 2 (TLR2) and TLR4 - in human cervix during pregnancy, term and preterm labor. Cervical biopsies were taken from 58 women: 20 at preterm labor, 24 at term labor, 10 at term not in labor and 4 from non-pregnant women. Real-time RT-PCR was used to quantify mRNA expression, and immunohistochemistry and ELISA for protein analysis. HMGB1, RAGE, TLR2 and TLR4 proteins were localized and their mRNA expression was detected in the cervix. There was more extranuclear HMGB1 in the cervical epithelium and stroma in preterm and term labor compared to the term not in labor. TLR2 mRNA expression was upregulated 5-fold in term labor and 3-fold in preterm labor compared to term not in labor and non-pregnant controls. There was lower expression of TLR2 and TLR4 mRNAs in preterm labor compared to term. Lower mRNA expression of HMGB1 was found in the subgroup with preterm premature rupture of membranes than in the rest of the preterm group, where levels were significantly higher than in term labor. In conclusion, extranuclear expression of HMGB1 during labor suggests a possible role of HMGB1 during the process of cervical ripening. Changes in expression of mRNAs encoding HMGB1, TLR2 and TLR4 in preterm labor suggest differences in the mechanism of cervical ripening at preterm and term delivery. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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- Dubicke, Aurelija
(författare)
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Preterm and term cervical ripening : studies on CRH, HMGB1, toll-like receptors, cytokines and matrix metalloproteinases
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. Despite the existing treatment, the frequency of PTB has not changed in the past thirty years. Incomplete understanding of the biological and pathophysiological mechanisms underlying preterm delivery is the major obstacle to preventing PTB. Cervical ripening is necessary for vaginal delivery, for which reason understanding of preterm cervical ripening is required for developing new treatment strategies. The overall aim of the work presented in this thesis was therefore to determine possible differences between preterm and term cervical ripening. Methods: Transvaginal cervical biopsies were obtained from women undergoing spontaneous delivery or elective caesarean section at preterm and term, and from non-pregnant women. Real-time RT-PCR was employed for analysis of mRNA, and immunohistochemistry, ELISA and Immulite for protein analysis. Corticotropin-releasing hormone (CRH), its binding protein (CRH-BP), its receptors (CRH-R1 and CRH-R2), matrix metalloproteinases (MMP) -1, -3, -8, -9, high-mobility group box protein 1 (HMGB1), receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), TLR4, interleukin (IL)-1alpha, IL1-beta, IL-12, IL-18, IL-4, IL-10 and IL-13 were analyzed in cervical tissue. Preterm and term cervical fibroblast cultures were established and the secretion of IL-8, MMP-1 and MMP-3 was measured after stimulation with CRH. Results: CRH, CRH-BP, CRH-R1, CRH-R2 and HMGB1 were identified in human cervical tissue for the first time. TLR2, TLR4, IL-10 and IL-12 were identified in the cervix for the first time in relation to pregnancy and labor. The distinct changes were determined in the cervix in labor irrespective of gestational age. There was downregulation of mRNA for CRH-BP, CRH-R2, RAGE, IL-12, IL-18, but upregulation of mRNA for TLR2, IL-10, IL-1beta, MMP-1, MMP-3 and MMP-9. More extranuclear staining of HMGB1 in stroma and empty nuclei in squamous epithelium were observed in labor. TLR2 and TLR4 tissue expression was lower in labor. IL-4 and IL-12 concentrations were lower, but soluble RAGE, IL-18, MMP-8 and MMP-9 were higher in labor. Differences between preterm and term cervical ripening were found: mRNA expression of TLR2, TLR4 and IL12 was lower in preterm labor, while IL-10 protein expression was higher in the cervical epithelium in preterm labor. Furthermore, preterm and term cervical fibroblasts showed different secretion patterns with higher levels of IL-8 and MMP-1, but lower levels of MMP-3, at preterm. CRH significantly increased the secretion of IL-8 in cervical fibroblasts. Subgroup analysis revealed some differences in association with preterm premature rupture of membranes (PPROM) and positive vaginal and/or urinary cultures. Conclusions: Preterm cervical ripening is an inflammatory process similar to cervical ripening at term. However, some differences still exist: these include downregulation of TLR2, TLR4 and IL-12 and higher levels of IL-10 in cervical epithelium. CRH and HMGB1 are probably involved in cervical ripening. Our results indicate that PPROM and PTL with infection could partly involve different mechanisms.
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- Dubicke, Aurelija, et al.
(författare)
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Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening
- 2010
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Ingår i: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 84:2, s. 176-185
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Tidskriftsartikel (refereegranskat)abstract
- Cervical ripening is necessary for successful delivery. Since cytokines are believed to be involved in this process, the aim of this study was to investigate possible changes in the mRNA and protein expression of pro-inflammatory cytokines (interleukin (IL)-1 alpha, IL-1 beta, IL-12, IL-18) and anti-inflammatory cytokines (IL-4, IL-10, IL-13)in the human cervix during pregnancy, term and preterm labor. Cervical biopsies were taken from 59 women: 21 at preterm labor, 24 at term labor, 10 at term not in labor and 4 from non-pregnant women. mRNA was analyzed with real-time RT-PCR and protein expression and/or secretion with immunohistochemistry and ELISA. There was an upregulation of mRNA for IL-10, IL-13, IL-1 alpha and IL-1 beta in the laboring groups, while mRNA for IL-12 and IL-18 was downregulated. IL-4 mRNA was detected more frequently, while IL-12 mRNA expression was lower, in the preterm labor group than in the term labor group. The protein levels of IL-4 and IL-12 were lower and IL-18 tended to be higher in the labor groups, while IL-10 protein levels were unaffected by labor. IL-4 protein levels were significantly higher in the preterm subgroup with bacterial infection than in the non-infected group. IL-10 had higher expression in squamous epithelium at preterm labor than at term. In conclusion, the major changes in pro-inflammatory and anti-inflammatory cytokine mRNA and protein expression in cervix occur during the labor process irrespective of the length of gestation. Our results indicate that dysregulation of anti-inflammatory cytokines in the human cervix could be involved in the pathogenesis of preterm labor.
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- Ekman-Ordeberg, Gunvor, et al.
(författare)
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Does low molecular weight heparin shorten term labor?
- 2010
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Ingår i: Acta obstetricia et gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 89:1, s. 147-50
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Tidskriftsartikel (refereegranskat)abstract
- Dalteparin, a low molecular weight heparin (LMWH), is given to pregnant women with thrombotic disorders. Clinical observations together with the documented changes of heparan sulfate proteoglycans in normal and protracted labor fostered the idea that LMWH shortens delivery time. Labor time was retrospectively determined among nulliparous pregnant women treated with dalteparin because of previous venous thromboembolism (VTE), thrombophilia or acute VTE during current pregnancy. Their labor time was compared to matched untreated controls. The proportion of instrumental deliveries and neonatal outcome was also compared. The dalteparin-treated group showed a significantly (30%) shorter labor time compared to matched controls. Total instrumental deliveries were the same in the two groups but operative intervention due to protracted labor was significantly less common in dalteparin-treated women. There was no difference in neonatal outcome. Dalteparin most likely shortens parturition time and may decrease the number of operative interventions due to protracted labor.
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