Cervical Remodeling/Ripening at Term and Preterm Delivery: The Same Mechanism Initiated by Different Mediators and Different Effector Cells

Abstract

BackgroundPremature cervical remodeling/ripening is believed to contribute to preterm delivery (PTD), the leading cause of perinatal morbidity and mortality. Despite considerable research, the causes of term and PTD remain unclear, and there is no effective treatment for PTD. We previously demonstrated that complement activation plays a causative role in cervical remodeling that leads to PTD in mice.Methodology/Principal FindingsHere we found that complement activation is not required for the physiological process that leads to term delivery in mice. Neither increased C3 cervical deposition nor increased C3a and C5a serum levels were observed at term. In addition, macrophages infiltration was found in PTD in contrast to term delivery were no leukocytes were found. Despite the different role of complement and different cellular effector cells, PTD and term delivery share a common dowsntream pathway characterized by increased metalloproteinases (MMPs) release and increased collagen degradation. However, different sources of MMPs were identified. Macrophages are the source of MMPs in PTD while cervical fibroblasts and columnar epithelial cells synthesize MMPs at term delivery. A dramatic diminution in serum progesterone levels precedes parturition at term but not in PTD, suggesting that progesterone withdrawal initiates cervical remodeling at term. On the other hand, MMPs release in PTD is triggered by C5a.Conclusion and SignificanceIn conclusion, preterm and term cervical remodeling occur through the same mechanism but they are initiated by different mediators and effector cells. That complement activation is required for PTD but not for the physiological process that leads to term delivery, suggests that complement is a potential specific biomarker and selective target to prevent PTD and thus avert neonatal mortality and morbidity.

Complement C5a Regulates Prolabor Mediators in Human Placenta1

“…Similarly, women with preterm delivery and intraamniotic infection have increased plasma C5a levels [10], tempting the hypothesis that C5a plays a role in the pathogenesis of preterm labor. It is of note that a recent study in mice found that the release of MMPs in preterm delivery is triggered by C5a [42]. In addition, this study also reported increased release of MMP9 in response to C5a in cervical macrophages in vitro.…”

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term

“…Such a pathway has been implicated in susceptibility to viral infections [69] and the pathological process of preterm labor [70][71][72][73][74], but not in the physiological process of labor at term. Therefore, this finding requires further investigation.…”

Pathway Markers for Pro-resolving Lipid Mediators in Maternal and Umbilical Cord Blood: A Secondary Analysis of the Mothers, Omega-3, and Mental Health Study

“…This may explain the increase in cord blood levels of 17-HDHA after exposure to labor, which requires activation of inflammatory pathways, compared to elective cesarean section (Gonzalez et al, 2011). Lipid mediators have also been found to be 10–100 times higher in serum compared to plasma (Colas et al, 2014).…”