This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cindrova-Davies, T. Articles by Burton, G. J. Search for Related Content PubMed PubMed Citation Articles by Cindrova-Davies, T. Articles by Burton, G. J.

(American Journal of Pathology. 2007;170:1511-1520.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061035

Nuclear Factor-B, p38, and Stress-Activated Protein Kinase Mitogen-Activated Protein Kinase Signaling Pathways Regulate Proinflammatory Cytokines and Apoptosis in Human Placental Explants in Response to Oxidative Stress

Effects of Antioxidant Vitamins

Tereza Cindrova-Davies^*, Olivera Spasic-Boskovic^*, Eric Jauniaux, D. Stephen Charnock-Jones and Graham J. Burton^*

From the Departments of Physiology, Development and Neuroscience^* and Obstetrics and Gynaecology, University of Cambridge, Cambridge; and the Academic Department of Obstetrics and Gynaecology, Royal Free and University College, London, United Kingdom

Preeclampsia is a potentially fatal complication of human pregnancy characterized by hypertension, proteinuria, and edema. Placental oxidative stress is a key element in the pathogenesis of the syndrome and results in the release of a cocktail of factors, including proinflammatory cytokines and apoptotic debris, that in turn cause activation of the maternal endothelium. The intermediary molecular mechanisms underlying this release are unknown, but they represent a potential target for therapeutic interventions. We examined activation of signaling pathways during hypoxia-reoxygenation of villous explants in vitro. Hypoxia-reoxygenation activated the p38 and stress-activated protein kinase mitogen-activated protein kinase (MAPK) and the nuclear factor-B pathways. Downstream consequences included increased tissue concentrations and secretion of tumor necrosis factor- and interleukin-1ß, increased expression of cyclooxygenase-2, and increased apoptosis. Administration of vitamins C and E to explants blocked activation of the p38 and stress-activated protein kinase MAPK and nuclear factor-B pathways. Vitamin administration or p38 pathway inhibition also reduced cyclooxygenase-2 expression, tumor necrosis factor- and interleukin-1ß secretion, and the levels of apoptosis. We conclude that oxidative stress is a potent inducer of placental synthesis and release of proinflammatory factors. Most of these effects are mediated through the p38 MAPK and nuclear factor-B pathways and can be effectively blocked by vitamins C and E in vitro.

This article has been cited by other articles:

				T. Cindrova-Davies, H.-W. Yung, J. Johns, O. Spasic-Boskovic, S. Korolchuk, E. Jauniaux, G. J. Burton, and D. S. Charnock-Jones Oxidative Stress, Gene Expression, and Protein Changes Induced in the Human Placenta during Labor Am. J. Pathol., October 1, 2007; 171(4): 1168 - 1179. [Abstract] [Full Text] [PDF]