Antenatal phosphodiesterase 4 inhibition restores postnatal growth and pulmonary development in a model of chorioamnionitis in rabbits

J Pharmacol Exp Ther. 2012 Mar;340(3):620-8. doi: 10.1124/jpet.111.179085. Epub 2011 Dec 7.

Abstract

Chorioamnionitis is implicated in the pathophysiology of bronchopulmonary disease, and the associated inflammatory response is responsible for adverse effects on alveolar development. The aim of this work was to analyze the effects of a phosphodiesterase 4 (PDE4)-selective inhibitor, rolipram (a modulator of the inflammatory response), in an experimental model of chorioamnionitis on pulmonary development and on the processes of infection and inflammation. Rabbit mothers were assigned to four groups: 1) saline serum inoculation (controls); 2) Escherichia coli intrauterine inoculation (C+); 3) rolipram infusion (R+); and 4) E. coli inoculation + rolipram infusion (C+R+). High rates of morbility and mortality were noticed in mothers and pups (5 of 13 pregnant rabbits in groups with rolipram). Alveolar development, inflammation, and infection were analyzed in pups at day 0 and day 5. At day 0, in the context of chorioamnionitis, rolipram significantly decreased birth weight (p < 0.01) relative to that of controls (p < 0.05). At day 5, weight normalized in group C+R+ but not in group C+ relative to controls (p < 0.001); moreover, alveolar airspace volume was preserved in group C+R+ but not in group C+ (p < 0.05). Interstitial volume decreased in group C+ versus controls (p < 0.05) but was preserved in group C+R+. Specific alveolar area was not significantly modified by rolipram. No significant difference was found concerning bronchoalveolar lavage cellularity, and all blood cultures remained sterile. In this model of impaired alveologenesis, rolipram significantly preserved specific alveolar density. However, PDE4 inhibition induced antenatal fetal demise and growth retardation.

MeSH terms

  • Animals
  • Chorioamnionitis / drug therapy*
  • Disease Models, Animal
  • Elastic Tissue / drug effects
  • Female
  • Lung / drug effects*
  • Lung / enzymology
  • Lung / growth & development
  • Lung Volume Measurements
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Pregnancy
  • Rabbits
  • Rolipram / pharmacology*
  • Weight Gain / drug effects

Substances

  • Phosphodiesterase 4 Inhibitors
  • Rolipram