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

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-kB-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.-Hadi, T., Bardou, M., Mace, G., Sicard, P., Wendremaire, M., Barrichon, M., Richaud, S., Demidov, O., Sagot, P., Garrido, C., Lirussi, F. Glutathione prevents preterm parturition and fetal death by targeting macrophage-induced reactive oxygen species production in the myometrium. FASEB J. 29, 2653-2666 (2015). www.fasebj.org

N-acetylcysteine attenuates lipopolysaccharide-induced impairment in lamination of Ctip2-and Tbr1- expressing cortical neurons in the developing rat fetal brain

“…Activated macrophages elevate cytotoxic molecules, such as free radical species and proinflammatory cytokines, which contribute to neurotoxicity in coculture systems3441 and in a murine model42. NAC is a known ROS scavenger that not only ameliorates LPS-induced ROS generation and inflammatory effects in amniotic fluid and placenta, but also increases fetal viability and reduces white matter injury3643.…”

“…Similarly, embryo weight was increased in the 25-μg/kg LPS group, and NAC returned this level close to control (Table 1). Previous studies suggest that LPS-induced oxidative stress and ROS contribute to fetal death3334. NAC may have the capacity to attenuate LPS-induced cerebral white matter injury37.…”

Human thioredoxin-1 attenuates the rate of lipopolysaccharide-induced preterm delivery in mice in association with its anti-inflammatory effect

“…In addition to these agents, antioxidants are believed to represent a promising treatment option, not only for preterm birth (7,14,24) but also for neonatal disorders, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and periventricular leukomalacia (25). We showed that TRX is one of the potential agents for intrauterine infection/inflammation by its antioxidant and anti-inflammatory properties.…”

Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity

“…In human gestational tissues (placenta, fetal membranes, and myometrium), treatment with antioxidants (curcumin, naringenin, or apigenin) reduced expression of LPS-induced IL-6, IL-8, and COX-237. In animal models, numerous antioxidants have shown beneficial effects on PTB, fetal death, and intrauterine growth restriction38394041. Thus, oxidative stress strongly correlates with PTB and other adverse birth outcomes, and therapies that reduce oxidative stress could have beneficial effects in reducing the risks of PTB and its associated complications.…”