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N-Acetyl-Cysteine Inhibits Phospholipid Metabolism, Proinflammatory Cytokine Release, Protease Activity, and Nuclear Factor-B Deoxyribonucleic Acid-Binding Activity in Human Fetal Membranes in Vitro

Department of Obstetrics and Gynecology, University of Melbourne, and Mercy Perinatal Research Center, Mercy Hospital for Women, East Melbourne, 3002 Victoria, Australia

Address all correspondence and requests for reprints to: Dr. Martha Lappas, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, 126 Clarendon Street, East Melbourne, 3002 Victoria, Australia. E-mail: mlappas{at}unimelb.edu.au.

The production of reactive oxygen species (ROS), prostaglandins (PGs), proinflammatory cytokines, and proteases has been implicated in the pathogenesis of term and preterm labor. The nuclear factor-B (NF-B) transcription pathway is activated by ROS and is a key regulator of PGs, proinflammatory cytokine release, and protease activity. N-Acetyl-cysteine (NAC) is an antioxidant that through its ability to scavenger ROS suppresses NF-B DNA-binding activity and resultant gene expression. The aim of this study was to elucidate the effect of NAC on NF-B DNA-binding activity, phospholipid metabolism, cytokine release, and protease activity from human fetal membranes. Human amnion and choriodecidua (n = 9 separate placentas) were treated with 0 (control), 5, 10, or 15 mM NAC in the presence of 10 µg/ml lipopolysaccharide. After 6-h incubation, the tissues were collected, NF-B DNA binding activity was assessed by gel shift binding assays, and matrix metalloproteinase-9 and urokinase-type plasminogen activator activity were determined by zymography. The incubation medium was collected and assayed for type II phospholipase A₂ tissue content, IL-6, IL-8, TNF, and 8-isoprostane release by ELISA. The release of PGF₂ was measured by RIA. Treatment of fetal membranes with NAC significantly suppressed lipopolysaccharide-stimulated type II phospholipase A₂ release and content; PGF₂, IL-6, IL-8, TNF, and 8-isoprostane release; and matrix metalloproteinase-9 and urokinase-type plasminogen activator enzyme activity and suppressed NF-B DNA-binding activity (by ANOVA, P < 0.05). The data presented in this study demonstrate that NAC inhibits an NF-B-activated pathway and subsequent phospholipid metabolism, proinflammatory cytokine release, and protease activity in human fetal membranes.

This work was supported by the Medical Research Foundation for Women and Babies and the National Health and Medical Research Council of Australia (Grant 114106).

Abbreviations: ECM, Extracellular matrix; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; NAC, N-acetyl-cysteine; NF-B, nuclear factor-B; PGF₂, prostaglandin F₂; PLA₂, phospholipase A₂; PPROM, prolonged premature rupture of membranes; ROS, reactive oxygen species; uPA, urokinase-type plasminogen activator.

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