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* Institut National de la Santé et de la Recherche Médicale, Unité 767, Paris, France;
Université René Descartes, Paris, France;
Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Maternité Port-Royal, Paris, France;
Institut Cochin, Plateforme de Morphologie/Histologie Animale, Unité 567, Unité Mixte de Recherche 8104, Paris, France;
¶ Laboratoire d’Immunologie, UPRES 1833, Paris, France; and
|| Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1198, ENVA, Centre National de la Recherche Scientifique, Formation de Recherche d’Emergence 2857, Biologie du Développement et Reproduction, Jouy en Josas, France
The aim of this study was to explore the anti-inflammatory properties of phosphodiesterase-4 (PDE4) inhibitors in vivo and their potential ability to prevent inflammation-induced preterm delivery. Indeed, intrauterine inflammation is the major etiology of very preterm delivery, the leading cause of neonatal mortality and morbidity. Intrauterine injection of Escherichia coli LPS in 15-day-pregnant mice induced an increase of PDE4 activity and PDE4B expression at the maternofetal interface, a rise of amniotic fluid levels of TNF-
, IL-1
, IL-6, and IL-10 and provoked massive preterm delivery and fetal demise. Selective PDE4 inhibition by rolipram prevented the rise in the proinflammatory cytokines. Following the nuclear translocation of the transcription factor NF
B, as a marker of cellular activation after the inflammatory challenge, showed a time-dependent sequential activation of the gestational tissues, from the uterine mesometrial to the fetal compartment, particularly in the glycogen-trophoblastic cells of the placenta. This activation was disrupted by PDE4 inhibition, and inflammation-induced preterm delivery and fetal demise were prevented. PDE4 selective inhibitors may thus represent a novel effective treatment to delay inflammation-induced preterm delivery and to prevent adverse outcomes in infants.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by March of Dimes Birth Defects Foundation Grant 6-FY03-6.
2 Address correspondence and reprint requests to Dr. Céline Méhats, Faculté de Pharmacie, Institut National de la Santé et de la Recherche Médicale, Unité 767, 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France. E-mail address: mehats{at}cochin.inserm.fr
3 Abbreviations used in this paper: PDE, phosphodiesterase; uNK, uterine NK; PAS, periodic acid-Schiff; PGHS, prostaglandin G/H synthase.
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