Phosphodiesterase 4 inhibition attenuates pulmonary inflammation in neonatal lung injury

¹ Dept of paediatrics, Division of Neonatology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands and
² Dept of paediatrics, Division of Neonatology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands and; and Dept of paediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.

^* To whom correspondence should be addressed. E-mail: g.t.m.wagenaar{at}lumc.nl.

	Abstract

Phosphodiesterase-4 (PDE4) inhibitors may offer novel therapeutic strategies in respiratory disease, including asthma and chronic obstructive pulmonary disease. Therefore, selective PDE4 inhibitors may also provide a therapeutic option for very preterm infants with bronchopulmonary dysplasia (BPD). We investigated the anti-inflammatory effect of two PDE4 inhibitors in a preterm rat model of hyperoxia-induced lung injury.

Preterm rat pups were exposed to room air, hyperoxia or hyperoxia and one of two PDE4 inhibitors: rolipram and piclamilast. The anti-inflammatory effects of prolonged PDE4 inhibitor therapy were investigated by studying survival, histopathology, fibrin deposition, alveolar vascular leakage and differential mRNA expression (real-time RT-PCR) of key genes involved in inflammation, alveolar enlargement, coagulation and fibrinolysis.

PDE4 inhibitor therapy prolonged median survival up to 7 days, reduced alveolar fibrin deposition, lung inflammation, and vascular leakage by decreasing the influx of monocytes and macrophages and protein efflux in bronchoalveolar lavage fluid. Analysis of mRNA expression of key genes involved in experimental BPD revealed a significant PDE4 inhibitor-induced improvement of genes involved in inflammation, fibrin deposition and alveolarization.

We conclude that PDE4 inhibition prolongs survival by inhibiting inflammation and reducing alveolar fibrin deposition in preterm rat pups with neonatal hyperoxic lung injury, whereby piclamilast outperformed rolipram.

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