Appropriate and timely cervical remodeling is key for successful birth. Premature cervical opening can result in preterm birth which occurs in 12.5% of pregnancies. Research focused on the mechanisms of term and preterm cervical remodeling is essential to prevent prematurity. This review highlights recent findings that better define molecular processes driving progressive disorganization of the cervical extracellular matrix. This includes studies that redefine the role of immune cells and identify diverse functions of the cervical epithelia and hyaluronan in remodeling. New investigations proposing that infection-induced premature cervical remodeling is distinct from the normal process are presented. Recent advances in our understanding of term and preterm cervical remodeling provide new directions for investigation and compel investigators to reevaluate currently accepted models. OverviewThe transformation of the cervix from a closed rigid structure to one that opens sufficiently for birth is an active dynamic process that begins long before the onset of labor. Better understanding of the molecular process of cervical remodeling is critical for the development of therapies to treat preterm birth and postterm pregnancies due to cervical malfunction. In this review, recent insights gained from studies in rodent models will be presented and contrasted with human studies. Although the mechanisms used to achieve the appropriate hormonal environment for each phase of cervical remodeling differ between human and rodent (Box 1), the end result is a similar endocrine environment; further, there is a growing body of evidence that molecular mechanisms of cervical remodeling are well conserved between these two species. This review highlights some of the recent findings in this area. Distinct phases of remodelingCervical remodeling can be loosely divided into four distinct but overlapping phases termed softening, ripening, dilation and postpartum repair (Table 1) [1,2]. Softening can be defined as the first measurable decline in the tensile strength or tissue compliance compared to nonpregnancy. Biomechanical studies in mice or digital exam in women indicate softening begins by day 12 of a 19 day gestation in mice and in the first trimester of pregnancy in women [1,3]. This phase is unique from the subsequent two phases in that softening is a relatively slow and incremental process taking place in a progesterone rich environment. Despite the progressive increase in compliance, tissue competence is maintained. Following softening, cervical ripening is a more accelerated phase characterized by maximal loss of tissue © 2010 Elsevier Ltd. All rights reservedCorresponding author: Mahendroo, M (mala.mahendroo@utsouthwestern.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is p...

Cervical remodeling during pregnancy and parturition is a single progressive process that can be loosely divided into four overlapping phases termed softening, ripening, dilation/labor, and post partum repair. Elucidating the molecular mechanisms that facilitate all phases of cervical remodeling is critical for an understanding of parturition and for identifying processes that are misregulated in preterm labor, a significant cause of perinatal morbidity. In the present study, biomechanical measurements indicate that softening was initiated between gestation days 10 and 12 of mouse pregnancy, and in contrast to cervical ripening on day 18, the softened cervix maintains tissue strength. Although preceded by increased collagen solubility, cervical softening is not characterized by significant increases in cell proliferation, tissue hydration or changes in the distribution of inflammatory cells. Gene expression studies reveal a potentially important role of cervical epithelia during softening and ripening in maintenance of an immunomucosal barrier that protects the stromal compartment during matrix remodeling. Expression of two genes involved in repair and protection of the epithelial permeability barrier in the gut (trefoil factor 1) and skin (serine protease inhibitor Kazal type 5) were increased during softening and/or ripening. Another gene whose function remains to be elucidated, purkinje cell protein 4, declines in expression as remodeling progressed. Collectively, these results indicate that cervical softening during pregnancy is a unique phase of the tissue remodeling process characterized by increased collagen solubility, maintenance of tissue strength, and upregulation of genes involved in mucosal protection.

In the current study, the mechanisms of premature cervical ripening in murine models of preterm birth resulting from infection or early progesterone withdrawal were compared with the process of term cervical ripening. Tissue morphology, weight, gene expression, and collagen content along with immune cell populations were evaluated. Premature ripening induced by the progesterone receptor antagonist mifepristone results from an acceleration of processes in place during term ripening as well as partial activation of proinflammatory and immunosuppressive processes observed during postpartum repair. In contrast to term or mifepristone-induced preterm ripening, premature ripening induced in an infection model occurs by a distinct mechanism which is dominated by an influx of neutrophils into the cervix, a robust proinflammatory response and increased expression of prostaglandin-cyclooxygenase-endoperoxide synthase 2, important in prostaglandin biosynthesis. Key findings from this study confirm that cervical ripening can be initiated by more than one mechanism and is not necessarily an acceleration of the physiologic process at term. These results will influence current strategies for identifying specific etiologies of preterm birth and developing subsequent therapies.

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Preterm birth occurs at a rate of 12.7% in the U.S. and is the primary cause of fetal morbidity in the first year of life as well as the cause of later health problems. Elucidation of mechanisms controlling cervical remodeling is critical for development of therapies to reduce the incidence of prematurity. The cervical extracellular matrix must be disorganized during labor to allow birth, followed by a rapid repair postpartum. Leukocytes infiltrate the cervix before and after birth and are proposed to regulate matrix remodeling during cervical ripening via release of proteolytic enzymes. In the current study, flow cytometry and cell sorting were used to determine the role of immune cells in cervical matrix remodeling before, during, and after parturition. Markers of myeloid cell differentiation and activation were assessed to define phenotype and function. Tissue monocytes and eosinophils increased in the cervix before birth in a progesterone-regulated fashion, whereas macrophage numbers were unchanged. Neutrophils increased in the postpartum period. Increased mRNA expression of Csfr1 and markers of alternatively activated M2 macrophages during labor or shortly postpartum suggest a function of M2 macrophages in postpartum tissue repair. Changes in cervical myeloid cell numbers are not reflected in the peripheral blood. These data along with our previous studies suggest that myeloid-derived cells do not orchestrate processes required for initiation of cervical ripening before birth. Additionally, macrophages with diverse phenotypes (M1 and M2) are present in the cervix and are most likely involved in the postpartum repair of tissue.