Characterizing the Cervical Response to Inflammation During Infection-Mediated Preterm Birth

Date

2017-11-08

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Abstract

Preterm birth, a delivery that occurs prior to 37 weeks of a 40 week gestation in women, is a leading cause of infant morbidity and mortality. Additionally, children born preterm who make it through their first year of life are at increased risk of medical complications throughout their lives. Costs associated with prematurity exceed $26 million each year in the United States alone, where nearly 1 in 10 babies is born preterm. The fact that preterm birth rates have only slight declined overall in the past 20 years can be attributed to the multiple, and most yet-to-be-identified, etiologies of the syndrome. More than 65% of all preterm births have no clinically identifiable cause. Of the premature deliveries with an identifiable cause, infection contributes to 40%. Regardless of the cause or timing of delivery, changes in the cervix precede the onset of labor. A better understanding of the pathological processes involved in premature cervical remodeling will allow for development of detection technologies and therapeutic approaches to preventing preterm birth. The goal of this study was to identify cervical pathways, distinctly regulated in response to inflammation, that lead to premature changes in extracellular matrix components, decreasing tissue biomechanical integrity and leading to preterm birth. Cervical elastic fiber ultrastructure becomes acutely disrupted in response to inflammation but not at term. RNA-seq studies identified enrichment of inflammasome activation and protease pathways in the cervix, both also exclusive to inflammation. Inflammasome-induced protease upregulation and subsequently increased activity targeting elastic fibers are potential mechanisms of premature cervical remodeling in response to inflammation, leading to preterm birth. These findings add to the understanding of how the tissue responds to inflammation and how this response can induce extracellular matrix changes that impact the biomechanical integrity of the cervix. Future investigations will focus on potential therapeutic approaches that target mechanisms upstream of protease activation to prevent disrupted extracellular matrix architecture. The effects of these studies have the potential to extend beyond first pregnancies impacted by infection; risk of preterm birth in subsequent pregnancies, which increases exponentially as the number of preterm deliveries a woman experiences increases, may also be lessened.

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Cervix Uteri, Lipopolysaccharides, Premature Birth, Transcriptome

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