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.
Highlights
The process of parturition has been extensively studied
In 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 preterm delivery (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 avert neonatal mortality and morbidity
Summary
The process of parturition has been extensively studied. the mechanisms responsible for the onset and progression of labor are multifactorial and not completely understood [1,2,3]. Among the important events contributing to labor is the ripening/ remodeling of the cervix [4,5,6]. We previously demonstrated that complement activation plays a crucial role in the cervical remodeling process that leads to preterm labor [7]. Using a mouse model of PTD induced by LPS we found that complement split product C5a attracts and activates macrophages to the cervix [7]. In response C5a, macrophages release metalloproteinases (MMPs) that degrade collagen, increasing the cervix distensibility and leading to PTD in mice [7]. Premature cervical remodeling/ripening is believed to contribute to preterm delivery (PTD), the leading cause of perinatal morbidity and mortality. We previously demonstrated that complement activation plays a causative role in cervical remodeling that leads to PTD in mice
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