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

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

Author information

1
*Institut National de la Santé et de la Recherche Médicale, U866, Lipides Nutrition Cancer, Dijon, France; Université de Bourgogne, Dijon, France; Centre Hospitalier Universitaire de Dijon, Dijon, France; Institut National de la Santé et de la Recherche Médicale Centre d'Investigations Cliniques 1432, Dijon, France; Service de Gynécologie & Obstétrique, Dijon, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France; Université Paul Sabatier, Centre Hospitalier Universitaire of Toulouse, Claudius Regaud Institute, Toulouse, France; and **Anti-cancer Center George-François Leclerc, Centre Georges François Leclerc, Dijon, France.
2
*Institut National de la Santé et de la Recherche Médicale, U866, Lipides Nutrition Cancer, Dijon, France; Université de Bourgogne, Dijon, France; Centre Hospitalier Universitaire de Dijon, Dijon, France; Institut National de la Santé et de la Recherche Médicale Centre d'Investigations Cliniques 1432, Dijon, France; Service de Gynécologie & Obstétrique, Dijon, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France; Université Paul Sabatier, Centre Hospitalier Universitaire of Toulouse, Claudius Regaud Institute, Toulouse, France; and **Anti-cancer Center George-François Leclerc, Centre Georges François Leclerc, Dijon, France frederic.lirussi@u-bourgogne.fr.

Abstract

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

PMID:
25757563
DOI:
10.1096/fj.14-266783
[Indexed for MEDLINE]

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