Glutathione prevents preterm parturition and fetal death by targeting macrophage-induced reactive oxygen species production in the myometrium

FASEB J. 2015 Jun;29(6):2653-66. doi: 10.1096/fj.14-266783. Epub 2015 Mar 10.


Preterm birth is an inflammatory process resulting from the massive infiltration of innate immune cells and the production of proinflammatory cytokines in the myometrium. However, proinflammatory cytokines, which induce labor in vivo, fail to induce labor-associated features in human myometrial cells (MCs). We thus aimed to investigate if reactive oxygen species (ROS) production could be the missing step between immune cell activation and MC response. Indeed, we found that ROS production is increased in the human preterm laboring myometrium (27% ROS producing cells, respectively, versus 2% in nonlaboring controls), with 90% ROS production in macrophages. Using LPS-stimulated myometrial samples and cell coculture experiments, we demonstrated that ROS production is required for labor onset. Furthermore, we showed that ROS are required first in the NADPH oxidase (NADPHox)-2/NF-κB-dependent macrophage response to inflammatory stimuli but, more importantly, to trigger macrophage-induced MCs transactivation. Remarkably, in a murine model of LPS-induced preterm labor (inducing delivery within 17 hours, with no pup survival), cotreatment with glutathione delayed labor onset up to 94 hours and prevented in utero fetal distress, allowing 46% pups to survive. These results suggest that targeting ROS production with the macrophage-permeable antioxidant glutathione could constitute a promising strategy to prevent preterm birth.

Keywords: antioxidant; chorioamnionitis; inflammation; preterm labor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Cell Line, Tumor
  • Cells, Cultured
  • Female
  • Fetal Death / prevention & control*
  • Gene Expression
  • Glutathione / administration & dosage
  • Glutathione / pharmacology*
  • Humans
  • Infant, Newborn
  • Lipopolysaccharides
  • Macrophages / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Myometrium / cytology
  • Myometrium / drug effects*
  • Myometrium / metabolism
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • NF-kappa B / metabolism
  • Obstetric Labor, Premature / chemically induced
  • Obstetric Labor, Premature / metabolism
  • Obstetric Labor, Premature / prevention & control*
  • Pregnancy
  • Reactive Oxygen Species / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Young Adult


  • Lipopolysaccharides
  • NF-kappa B
  • Reactive Oxygen Species
  • NADPH Oxidases
  • Glutathione