Attenuation of Lipopolysaccharide-Induced Inflammatory Response and Phospholipids Metabolism at the Feto-Maternal Interface by N-Acetyl Cysteine

Abstract

Maternal microbial infections cause adverse fetal developmental outcomes including embryonic resorption, intrauterine fetal death, and preterm labor. Recent studies demonstrated that oxidativestress plays an important role in chorioamniotitis pathogenesis. Herein we investigated the effect of N-acetyl cysteine (NAC) on lipopolysaccharide (LPS)-induced preterm labor and fetal demise in murine model. Lipopolysaccharide exposure at embryonic day 18 demonstrated an increase in the abortion rate and fetal demise in pregnant rats. This was associated with increase in an inflammatory response (cytokines, chemokines, and iNOS expression) and infiltration of leukocytes (monocytes and polymorphonuclear cells) in the placenta. There was increased expression of cytosolic and secretary phospholipase A2 with increased secretion of prostaglandin-2 and leukotriene B4 in the placenta, suggestive of increased metabolism of phospholipids. In addition, expression of cycloxygenase-2 and malondialdehyde production (oxidative-stress marker) was increased in the placenta. Conversely, NAC pretreatment abolished these effects of LPS in the placenta. Collectively, these data provide evidence that LPS-induced increased inflammation and metabolism of phospholipids at the feto-maternal interface (placenta) is critical for preterm labor and fetal demise during maternal microbial infections which could be blocked by antioxidant-based therapies. (Pediatr Res 64: [334][335][336][337][338][339] 2008)

Oxidative Stress: A Potential Therapeutic Target in Placental Malaria

“…In keeping with the observed elevated expression of Sod3 , which was suggestive of extracellular oxidative stress, mice were first treated with NAC, an extracellular reactive oxygen scavenger. Although accumulation of maternal inflammatory monocytes and macrophages, which might contribute ROS, is not evident in placentas of P. chabaudi AS–infected pregnant B6 mice (17), an NAC treatment approach was rationalized by work in a rat model of LPS-induced preterm labor and fetal demise, which responded positively to NAC pretreatment (54) at the same concentrations used in this study. Contrary to expectations, however, NAC mediated no protective effect in malaria-infected mice, and in fact, appeared to be embryotoxic.…”

Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response

“…4). Histopathological (Carpentier et al, 2011; Fatemi et al, 2011; Girard et al, 2010) and oxidative stress activity (Paintlia et al, 2008) in the placenta following MIA can disrupt the maternal/placental transfer of nutrients to the fetus leading to transient fetal hypoxia. Carpentier et al (2011) showed evidence consistent with reduced oxygen supply to the fetal brain following maternal LPS administration on gestational day 12.5 in the mouse.…”

Effects of 4-Hydroxy-2-Nonenal, a Major Lipid Peroxidation-Derived Aldehyde, and N-Acetylcysteine on the Cyclooxygenase-2 Expression in Human Uterine Myometrium

“…The effect of NAC on lipopolysaccharide (LPS)-induced preterm labor and fetal demise in murine model was investigated. NAC pretreatment abolished these effects of LPS in the placenta [38]. We then investigated the effect of NAC on 4-HNE-induced COX-2 expression.…”