Activation of the epithelial sodium channel (ENaC) leads to cytokine profile shift to pro‐inflammatory in labor

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/PGE 2 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. Synopsis This study reveals a novel role for the epithelial sodium channel (ENaC) in transducing the mechanical signal from uterine contractions that results in production of pro‐inflammatory cytokines during labor. ENaC has the potential to be targeted for the prevention and treatment of preterm labor. ENaC expression is increased and its channel function is activated in the uterus during labor in mice. Mechanical stimulation activates ENaC, which leads to activation of the transcription factor CREB, and subsequent production of pro‐inflammatory cytokines/factors in uterine epithelial cells. ENaC expression is also increased 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. ENaC is significantly and positively correlated with labor‐associated pro‐inflammatory factors in human maternal‐fetus tissue/blood collected at onset of birth in women in labor only. Graphical Abstract This study reveals a novel role for the epithelial sodium channel (ENaC) in transducing the mechanical signal from uterine contractions that results in production of pro‐inflammatory cytokines during labor. ENaC has the potential to b