Cervical epithelial damage and preterm birth
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Preterm birth is the leading cause of neonatal mortality and morbidity. The uterine cervix is key in maintaining a healthy pregnancy. Excisional procedures for the treatment of cervical intraepithelial neoplasia (CIN) are associated with preterm birth (PTB), but underlying mechanisms are yet to be described. Intrauterine infection is involved in 40% of PTB and cervical damage is likely to facilitate ascending infection with vaginal bacteria. The aim of this thesis was to establish and characterise an in vitro and in vivo model of cervical damage to study its interplay with ascending infection. For this, the surfactant N-9 was used as a damage agent. N-9 was found to reduce the endocervical epithelial cells’ viability and compromise their epithelial permeability in vitro. When vaginally administered in pregnant C57Bl/6 mice, N-9 disrupted the structural integrity of the cervical epithelium, caused an influx of neutrophils and resulted in increased cell proliferation in the basement membrane of the cervix. Similar where the findings in the vaginal epithelium. However, N-9-induced epithelial damage had no effect on timing of delivery or pup survival. Following vaginal infection with a luciferase-expressing Ureaplasma parvum, mice previously treated with N-9 exhibited higher rates of ascending infection, with increased bioluminescence signal in the upper reproductive tract. They also demonstrated higher bacterial titres in the amniotic fluid and higher bacterial product copy numbers in the reproductive tissues. This resulted in increased preterm birth rates among mice in this group compared to vehicle-treated controls. Infection with Ureaplasma parvum was characterised by an inflammatory response in the uterus, the placenta and the fetal membranes with increased expression of the proinflammatory cytokines TNFa, IL-1b, CXCL-1 and CXCL-2. This effect may be mediated by TLR2, the expression of which was also shown to increase accordingly. Overall, these findings suggest that cervical epithelial damage facilitates ascending infection. This is a potential mechanism explaining the higher PTB incidence among women treated for CIN. The robust model of cervical epithelial damage during pregnancy described in this thesis can be used to study the barrier function of the cervix and its interplay with ascending infection in future studies.