PDE4 inhibition prevents preterm delivery induced by an intrauterine inflammation.
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-alpha, IL-1beta, 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 NFkappaB, 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.
Schmitz
Thomas
T
Institut National de la Santé et de la Recherche Médicale Unité 767, 4 Avenue de l'Observatoire, 75270 Paris Cedex 06, France.
Souil
Evelyne
E
Hervé
Roxane
R
Nicco
Carole
C
Batteux
Frédéric
F
Germain
Guy
G
Cabrol
Dominique
D
Evain-Brion
Danièle
D
Leroy
Marie-Josèphe
MJ
Méhats
Céline
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D020070:Cervical Ripening / Q000187:drug effects / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000097:blood; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D021381:Protein Transport; D020889:Rolipram / Q000494:pharmacology; D014591:Uterine Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D014599:Uterus / Q000473:pathology
D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011374:Progesterone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram