Abstract
Maternal microbial infections cause adverse fetal developmental outcomes including embryonic resorption, intrauterine fetal death, and preterm labor. Recent studies demonstrated that oxidative-stress 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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- COX-2:
-
cysloxygenase-2
- ICAM-1:
-
intracellular adhesion molecule-1
- LPS:
-
lipopolysaccharide
- LTB4:
-
leukotriene B4
- MDA:
-
malionaldehyde
- NAC:
-
N-acetyl cysteine
- PLA2:
-
phospholipase 2
- VCAM-1:
-
vascular adhesion molecule-1
References
Mitchell MD, Edwin SS, Lundin-Schiller S, Silver RM, Smotkin D, Trautman MS 1993 Mechanism of interleukin-1 beta stimulation of human amnion prostaglandin biosynthesis: mediation via a novel inducible cyclooxygenase. Placenta 14: 615–625
Dowling DD, Romero RJ, Mitchell MD, Lundin-Schiller S 1991 Isolation of multiple substances in amniotic fluid that regulate amnion prostaglandin E2 production: the effects of gestational age and labor. Prostaglandins Leukot Essent Fatty Acids 44: 253–255
Fortunato SJ, Menon RP, Swan KF, Menon R 1996 Inflammatory cytokine (interleukins 1, 6 and 8 and tumor necrosis factor-alpha) release from cultured human fetal membranes in response to endotoxic lipopolysaccharide mirrors amniotic fluid concentrations. Am J Obstet Gynecol 174: 1855–1861; discussion 1861–1862
Farrugia W, Nicholls L, Rice GE 1999 Effect of bacterial endotoxin on the in vitro release of Type II phospholipase-A2 and prostaglandin E2 from human placenta. J Endocrinol 160: 291–296
Anteby EY, Johnson RD, Huang X, Dryden DK, Nelson DM, Sadovsky Y 1998 Lipopolysaccharide enhances the transcription of prostaglandin H synthase-2 gene in primary human trophoblasts. Am J Obstet Gynecol 178: 469–473
O'Sullivan AM, Dore CJ, Boyle S, Coid CR, Johnson AP 1988 The effect of campylobacter lipopolysaccharide on fetal development in the mouse. J Med Microbiol 26: 101–105
Lappas M, Permezel M, Georgiou HM, Rice GE 2004 Regulation of phospholipase isozymes by nuclear factor-kappaB in human gestational tissues in vitro. J Clin Endocrinol Metab 89: 2365–2372
Neuschwander-Tetri BA, Bellezzo JM, Britton RS, Bacon BR, Fox ES 1996 Thiol regulation of endotoxin-induced release of tumour necrosis factor alpha from isolated rat Kupffer cells. Biochem J 320: 1005–1010
Verhasselt V, Vanden Berghe W, Vanderheyde N, Willems F, Haegeman G, Goldman M 1999 N-acetyl-l-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition. J Immunol 162: 2569–2574
Pahan K, Sheikh FG, Namboodiri AM, Singh I 1998 N-acetyl cysteine inhibits induction of no production by endotoxin or cytokine stimulated rat peritoneal macrophages, C6 glial cells and astrocytes. Free Radic Biol Med 24: 39–48
Song M, Kellum JA, Kaldas H, Fink MP 2004 Evidence that glutathione depletion is a mechanism responsible for the anti-inflammatory effects of ethyl pyruvate in cultured lipopolysaccharide-stimulated RAW 264.7 cells. J Pharmacol Exp Ther 308: 307–316
Sekhon B, Sekhon C, Khan M, Patel SJ, Singh I, Singh AK 2003 N-acetyl cysteine protects against injury in a rat model of focal cerebral ischemia. Brain Res 971: 1–8
Victor VM, Rocha M, De la Fuente M 2003 N-acetylcysteine protects mice from lethal endotoxemia by regulating the redox state of immune cells. Free Radic Res 37: 919–929
Jatana M, Singh I, Singh AK, Jenkins D 2006 Combination of systemic hypothermia and N-acetylcysteine attenuates hypoxic-ischemic brain injury in neonatal rats. Pediatr Res 59: 684–689
Paintlia MK, Paintlia AS, Barbosa E, Singh I, Singh AK 2004 N-acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain. J Neurosci Res 78: 347–361
Paintlia AS, Paintlia MK, Singh AK, Stanislaus R, Gilg AG, Barbosa E, Singh I 2004 Regulation of gene expression associated with acute experimental autoimmune encephalomyelitis by Lovastatin. J Neurosci Res 77: 63–81
Bell MJ, Hallenbeck JM, Gallo V 2004 Determining the fetal inflammatory response in an experimental model of intrauterine inflammation in rats. Pediatr Res 56: 541–546
Huleihel M, Amash A, Sapir O, Maor E, Levy S, Katz M, Dukler D, Myatt L, Holcberg G 2004 Lipopolysaccharide induces the expression of interleukin-1alpha distinctly in different compartments of term and preterm human placentae. Eur Cytokine Netw 15: 30–36
Hagberg H, Mallard C, Jacobsson B 2005 Role of cytokines in preterm labour and brain injury. BJOG 112: 16–18
Romero R, Sepulveda W, Kenney JS, Archer LE, Allison AC, Sehgal PB 1992 Interleukin 6 determination in the detection of microbial invasion of the amniotic cavity. Ciba Found Symp 167: 205–220; discussion 220–223.
Radi ZA, Kehrli ME Jr Ackermann MR 2001 Cell adhesion molecules, leukocyte trafficking, and strategies to reduce leukocyte infiltration. J Vet Intern Med 15: 516–529
Esplin MS, Romero R, Chaiworapongsa T, Kim YM, Edwin S, Gomez R, Mazor M, Adashi EY 2005 Monocyte chemotactic protein-1 is increased in the amniotic fluid of women who deliver preterm in the presence or absence of intra-amniotic infection. J Matern Fetal Neonatal Med 17: 365–373
Proost P, Wuyts A, van Damme J 1996 The role of chemokines in inflammation. Int J Clin Lab Res 26: 211–223
Denison FC, Kelly RW, Calder AA, Riley SC 1998 Cytokine secretion by human fetal membranes, decidua and placenta at term. Hum Reprod 13: 3560–3565
Callejas NA, Casado M, Bosca L, Martin-Sanz P 1999 Requirement of nuclear factor kappaB for the constitutive expression of nitric oxide synthase-2 and cyclooxygenase-2 in rat trophoblasts. J Cell Sci 112: 3147–3155
Candelario-Jalil E, Gonzalez-Falcon A, Garcia-Cabrera M, Alvarez D, Al-Dalain S, Martinez G, Leon OS, Springer JE 2003 Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia. J Neurochem 86: 545–555
Yamazaki K, Endo T, Kitajima Y, Manase K, Nagasawa K, Honnma H, Hayashi T, Kudo R, Saito T 2006 Elevation of both cyclooxygenase-2 and prostaglandin E2 receptor EP3 expressions in rat placenta after uterine artery ischemia-reperfusion. Placenta 27: 395–401
Miyaura C, Inada M, Matsumoto C, Ohshiba T, Uozumi N, Shimizu T, Ito A 2003 An essential role of cytosolic phospholipase A2alpha in prostaglandin E2-mediated bone resorption associated with inflammation. J Exp Med 197: 1303–1310
Perkins DJ, Kniss DA 1997 Tumor necrosis factor-alpha promotes sustained cyclooxygenase-2 expression: attenuation by dexamethasone and NSAIDs. Prostaglandins 54: 727–743
Victor VM, De la Fuente M 2003 Immune cells redox state from mice with endotoxin-induced oxidative stress. Involvement of NF-kappaB. Free Radic Res 37: 19–27
Biri A, Kavutcu M, Bozkurt N, Devrim E, Nurlu N, Durak I 2006 Investigation of free radical scavenging enzyme activities and lipid peroxidation in human placental tissues with miscarriage. J Soc Gynecol Investig 13: 384–388
Cai Z, Pan ZL, Pang Y, Evans OB, Rhodes PG 2000 Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr Res 47: 64–72
Tsuji F, Miyake Y, Aono H, Kawashima Y, Mita S 1999 Effects of bucillamine and N-acetyl-l-cysteine on cytokine production and collagen-induced arthritis (CIA). Clin Exp Immunol 115: 26–31
Rahman A, Kefer J, Bando M, Niles WD, Malik AB 1998 E-selectin expression in human endothelial cells by TNF-alpha-induced oxidant generation and NF-kappaB activation. Am J Physiol 275: L533–L544
Acknowledgements
We thank all members of our laboratory for their valuable comments and help during the course of this study. We thank especially Dr. Shalendra Giri, PhD, for detection of PGE2 and LTB4 in the placental tissue and Dr. Jennifer G. Schnellmann, PhD, for critical reading of this article.
Author information
Authors and Affiliations
Additional information
This study was supported in part by grants from the National Institutes of Health: NS-22576, NS-34741, NS-37766, NS-40810, and NCRR grants C06 RR018823 and C06 RR015455 from the Extramural Research Facilities Program.
Rights and permissions
About this article
Cite this article
Paintlia, M., Paintlia, A., Singh, A. et al. Attenuation of Lipopolysaccharide-Induced Inflammatory Response and Phospholipids Metabolism at the Feto-Maternal Interface by N-Acetyl Cysteine. Pediatr Res 64, 334–339 (2008). https://doi.org/10.1203/PDR.0b013e318181e07c
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e318181e07c
This article is cited by
-
Maternal supply of cysteamine alleviates oxidative stress and enhances angiogenesis in porcine placenta
Journal of Animal Science and Biotechnology (2021)
-
N-Acetylcysteine Attenuates Lipopolysaccharide-Induced Osteolysis by Restoring Bone Remodeling Balance via Reduction of Reactive Oxygen Species Formation During Osteoclastogenesis
Inflammation (2020)
