Cervical ripening : an inflammatory process involving cytokines, metalloproteinases and foetal fibronectin

Abstract

The aim of the thesis was to identify cytokines, metalloproteinases and foetal fibronectin in human cervical tissue and to investigate if changes are of importance for the final cervical ripening. The human cervical ripening is a prerequisite for a normal start and progress of labour. The cervix uteri is mainly composed of fibrous connective tissue, that undergoes an extensive remodelling during the entire pregnancy. This process, referred to as cervical ripening changes into a rapid final remodelling just preceding partus. Hormones as oestrogen, progesterone and prostaglandins are involved in the ripening process though the mechanism is still unclear. This thesis focuses on the involvement of inflammatory mediators such as the cytokines, as well as the presence of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) during the cervical ripening process. A possible foetal influence is also studied by evaluating if foetal fibronectin in cervical mucus and tissue could be involved in cervical ripening. Cervical biopsies were obtained transvaginally from term pregnant women with unripe cervices, from postpartum women with normal vaginal delivery and from non-pregnant women.

mRNA and protein levels of interleukin-8 (IL-8), interleukin-6 (IL-6) and granulocyte colony stimulating factor (G-CSF) were analysed, and IL-8 was localized immunohistochemically. A highly significant upregulation of all these cytokines were seen in parallel with cervical ripening and the immunohistochemistry confirmed it with abundant staining in the pos partum sections. These data demonstrate cervical ripening to be similar to an inflammatory process. Protein levels for matrix metal loproteinase (MMP)-1, -3 and -8 were analysed and MMP-8 (leucocyte derived collagenase) increased significantly concomitantly with cervical ripening whereas MMP-1 and MMP-3 were unchanged at low levels. The immunohistochemistry showed increased staining in pregnant compared to non-pregnant cervix for MMP-8 as well as MMP-1 and MMP-3 and also tissue inhibitor of matrix metalloproteinases (TIMP)-1 and TIMP-2 staining increased. Thus, the released leucocyte derived collagenase MMP-8 is involved in cervical ripening, and MMP-1, MMP-3, TIMP-1 and TIMP-2 seems also to be important in the extracellular matrix remodelling during pregnancy. Foetal fibronectin levels were analysed in cervical mucus from term pregnant women, and were found to increase during spontaneous as well as after PGE2 induced cervical ripening. Foetal fibronectin could also be localized in pregnant cervical tissue, where foetal fibronectin immunoflurescence were seen in glandular epithelia in both the unripe and ripe cervical tissue. Therefore, the foetal fibronectin levels in cervical mucus can be correlated to cervical ripening.

Conclusively, the increase of IL-8, IL-6, G-CSF and MMP-8 in the human cervix during the ripening process, demonstrates cervical ripening as an inflammatory reaction. Furthermore, a foetal influence on the cervical remodelling is suggested, since the foetal fibronectin can be identified in the ripening cervix, and levels of foetal fibronectin concomitantly increase in cervical mucus both after spontaneous and PGE2-induced cervical ripening.