Department of Obstetrics and Gynecology and Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Biol Reprod. 2018 Mar 1;98(3):408-421. doi: 10.1093/biolre/iox180.
With half a million babies born preterm each year in the USA and about 15 million worldwide, preterm birth (PTB) remains a global health issue. Preterm birth is a primary cause of infant morbidity and mortality and can impact lives long past infancy. The fact that there are numerous, and many currently unidentified, etiologies of PTB has hindered development of tools for risk evaluation and preventative therapies. Infection is estimated to be involved in nearly 40% of PTBs of known etiology; therefore, understanding how infection-mediated inflammation alters the cervical milieu and leads to preterm tissue biomechanical changes are questions of interest. Using RNA-seq, we identified enrichment of components involved in inflammasome activation and unique proteases in the mouse cervix during lipopolysaccharide (LPS)-mediated PTB and not physiologically at term before labor. Despite transcriptional induction of inflammasome components, there was no evidence of functional activation based on assessment of mature IL1B and IL18 proteins. The increased transcription of proteases that target both elastic fibers and collagen and concentration of myeloid-derived cells capable of protease synthesis in the cervical stroma support the structural disruption of elastic fibers as a functional output of protease activity. The recent demonstration that elastic fibers contribute to the biomechanical function of the pregnant cervix suggests their protease-induced disruption in the infection model of LPS-mediated PTB and may contribute to premature loss of mechanical competency and preterm delivery. Collectively, the transcriptomics and ultrastructural data provide new insights into the distinct mechanisms of premature cervical remodeling in response to infection.
每年美国有五十万婴儿早产，全世界约有一千五百万婴儿早产，因此早产仍然是一个全球性的健康问题。早产是婴儿发病率和死亡率的主要原因，并且会对婴儿期后的生活产生影响。由于早产有许多病因，其中许多目前尚未确定，这阻碍了风险评估和预防治疗工具的发展。据估计，感染约占病因明确的早产的 40%；因此，了解感染介导的炎症如何改变宫颈环境并导致早产组织生物力学变化，是一个令人关注的问题。我们使用 RNA-seq 技术，在 LPS 介导的早产小鼠宫颈中发现了参与炎症小体激活和独特蛋白酶的成分富集，而在生理足月未分娩前则没有。尽管炎症小体成分的转录诱导，但基于成熟的 IL1B 和 IL18 蛋白的评估，没有证据表明其功能激活。靶向弹性纤维和胶原蛋白的蛋白酶的转录增加，以及能够在宫颈基质中合成蛋白酶的髓样细胞的浓度增加，支持弹性纤维的结构破坏是蛋白酶活性的功能输出。最近的研究表明，弹性纤维有助于妊娠宫颈的生物力学功能，这表明它们在 LPS 介导的感染模型中的早产中被蛋白酶诱导破坏，可能导致机械能力过早丧失和早产。总的来说，转录组学和超微结构数据为感染引起的早产宫颈重塑的独特机制提供了新的见解。
