RESUMO
Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. Despite the current treatment procedures, the incidence of PTB has not changed in the past thirty years. Incomplete understanding of the biological and patophysiological mechanisms underlying preterm delivery is the major obstacle to prevent PTB. Cervical ripening is necessary for vaginal delivery and understanding of preterm cervical ripening is required for developing new treatment strategies. Several important substances such as HMGB1 and its receptors, CRH and its receptors and numerous cytokines are localized in the cervix and undergo distinct changes in labour. Other important -molecules, such as CRH, CRH-BP, CRH-R1, CRH-R2, HMGB1, TLR2, TLR4, IL-10, IL-12, are localized in the cervical epithelium, also indicating their role in the process of cervical ripening during labour. Furthermore, CRH stimulates IL-8 secretion from both preterm and term cervical fibroblasts. Recent studies from our group show that major -inflammatory changes occur in the cervix at labour irrespective of gestational age. This indicates that cervical ripening at both term and preterm is an inflammatory process even if no infection is present. However, preterm cervical ripening still entails some differences from term cervical ripening, for example in the down-regulation of mRNA expression of Toll-like receptors (TLR-2 and TLR-4) and IL-12, higher levels of IL-10 in cervical epithelium, and presents different secretion patterns of cervical fibroblasts. Moreover, preterm cervical ripening, like preterm delivery itself, is a multifactorial disorder with pathways which are partly different from those involved in PPROM and infected preterm labour.
RESUMO
The aims of the present study were to compare the levels of mRNA and protein expression of matrix metalloproteinase (MMP)-1, -3, -8 and -9 in human cervical tissue in preterm and term labor as well as not in labor and to determine if corticotropin-releasing hormone (CRH) has an effect on MMP-1, -3 and interleukin (IL)-8 secretion in both preterm and term cervical fibroblasts. Cervical biopsies were taken from 60 women: 18 at preterm labor, 7 at preterm not in labor, 18 at term labor and 17 at term not in labor. ELISA and Immulite were used for protein and real-time RT-PCR for mRNA analysis. Cervical fibroblast cultures were incubated for 18 h with different CRH concentrations (10(-13)-10(-6) M). The mRNA expression of MMP-1, -3 and -9 was higher in laboring groups compared with term not in labor. Protein levels of MMP-8 and -9 were higher in term in labor group compared with non-laboring groups. There were no significant differences in mRNA and protein expression between the preterm and respective term control groups. CRH significantly increased secretion of IL-8 in preterm and term cervical fibroblasts compared with controls. The secretion of IL-8 and MMP-1 was significantly higher and MMP-3 secretion lower in preterm cervical fibroblasts. In conclusion, cervical ripening at preterm seems to be a similar inflammatory process as at term with CRH involved. However, preterm and term cervical fibroblasts might have different phenotypes based on different secretion patterns of IL-8, MMP-1 and MMP-3.
