Detrimental Effects of an Inhaled Phosphodiesterase-4 Inhibitor on Lung Inflammation in Ventilated Preterm Lambs Exposed to Chorioamnionitis Are Dose Dependent

Matthias C. Huetten*, Markus Fehrholz, Franziska M. Konrad, Daan Ophelders, Clementine Kleintjes, Barbara Ottensmeier, Owen Brad Spiller, Kirsten Glaser, Boris W. Kramer, Steffen Kunzmann

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Web of Science)

Abstract

Background: Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation. Methods: Twenty-one preterm lambs were surgically delivered preterm at 129 days after 7 days intrauterine exposure to UP. Sixteen animals were subsequently ventilated for 24 hours and received endotracheal surfactant and intravenous caffeine citrate. Ten animals were randomized to receive twice a high (10 mu g/kg) or low dose (1 mu g/kg) of nebulized PDE4 inhibitor. Results: Nebulization of high, but not low, doses of PDE4 inhibitor led to a significant decrease in pulmonary PDE activity, and was associated with lung injury and vasculitis, influx of neutrophils, and increased proinflammatory cytokine messenger RNA levels. Conclusion: Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population.

Original languageEnglish
Pages (from-to)396-404
Number of pages9
JournalJournal of Aerosol Medicine and Pulmonary Drug Delivery
Volume32
Issue number6
DOIs
Publication statusPublished - Dec 2019

Keywords

  • bronchopulmonary dysplasia
  • lung injury
  • mechanical ventilation of neonates
  • PDE4 inhibitors
  • prematurity
  • BRONCHOPULMONARY DYSPLASIA
  • NEBULIZED PENTOXIFYLLINE
  • PULMONARY-DISEASE
  • PDE4 INHIBITOR
  • INJURY
  • COLONIZATION
  • MECHANISMS
  • EXPRESSION
  • TOXICITY
  • INFANTS

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