Abstract
The shift of cytokine profile from anti‐ to pro‐inflammatory is the most recognizable sign of labor, although the underlying mechanism remains elusive. Here, we report that the epithelial sodium channel (ENaC) is upregulated and activated in the uterus at labor in mice. Mechanical activation of ENaC results in phosphorylation of CREB and upregulation of pro‐inflammatory cytokines as well as COX‐2/PGE2 in uterine epithelial cells. ENaC expression is also upregulated in mice with RU486‐induced preterm labor as well as in women with preterm labor. Interference with ENaC attenuates mechanically stimulated uterine contractions and significantly delays the RU486‐induced preterm labor in mice. Analysis of a human transcriptome database for maternal–fetus tissue/blood collected at onset of human term and preterm births reveals significant and positive correlation of ENaC with labor‐associated pro‐inflammatory factors in labored birth groups (both term and preterm), but not in non‐labored birth groups. Taken together, the present finding reveals a pro‐inflammatory role of ENaC in labor at term and preterm, suggesting it as a potential target for the prevention and treatment of preterm labor.
Highlights
Labor or parturition, the end step of pregnancy, remains poorly understood (Muglia & Katz, 2010; Rubens et al, 2014), which accounts for the lack of effective method to prevent or predict preterm labor, a leading cause of neonatal death and disability (Liu et al, 2012; Iams, 2014b; Romero et al, 2014)
ENaC activation by embryo-released protease has been shown to result in membrane depolarization, Ca2+ influx, and phosphorylation of cAMP response element binding protein (CREB), a key transcription factor for cyclooxygenase 2 (COX-2), and enhanced production/ release of prostaglandins E 2 (PGE2) required for embryo implantation (Ruan et al, 2012)
Similar to its activation by protease, the present results show that the stretch-induced activation of ENaC leads to phosphorylation of CREB and COX-2/PGE2 (Fig 2)
Summary
The end step of pregnancy, remains poorly understood (Muglia & Katz, 2010; Rubens et al, 2014), which accounts for the lack of effective method to prevent or predict preterm labor, a leading cause of neonatal death and disability (Liu et al, 2012; Iams, 2014b; Romero et al, 2014). Among the recognized maternal or fetal derived signals associated with the initiation of labor, mechanical forces generated by either the growing fetus or initial uterine contractions are believed to be important (Lye et al, 2001). Mechanical stimulations are observed to induce uterine production of pro-inflammatory cytokines (e.g., IL-8; Maehara et al, 1996; Loudon et al, 2004; Shynlova et al, 2008) and prostaglandins (PGs; Challis et al, 2000; Sooranna et al, 2004), which in turn potently evoke uterine contractions (Wray, 1993) and may underlie a positive-feedback loop resulting in increasingly powerful expelling forces required for labor (Wray, 1993; Lye et al, 2001). Epithelial cells lining the uterine cavity as part of the decidua are believed to be a source of PGs at term (Dong et al, 1996; Olson, 2003; Satoh et al, 2013), whether and how these epithelial cells play a role in the process of labor is not well studied
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