Inhibition of PDE4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia

¹ University of Giessen Lung Center (UGLC), Giessen, Germany
² Erasmus MC-Sophia, Dept of Paediatric Surgical Intensive Care, Rotterdam, The Netherlands
³ Dept of Paediatrics, University Hospital Giessen, Giessen, Germany
⁴ University of Giessen Lung Center (UGLC), Giessen, Germany; and Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

^* To whom correspondence should be addressed. E-mail: ralph.schermuly{at}mpi-bn.mpg.de.

	Abstract

Bronchopulmonary dysplasia (BPD) is characterised by impaired alveolarisation, inflammation, and aberrant vascular development. Phosphodiesterase (PDE) inhibitors can influence cell proliferation, antagonise inflammation, and restore vascular development and homeostasis, suggesting a therapeutic potential in BPD.

To investigate PDE expression in the lung of hyperoxia-exposed mice, and assess the viability of PDE4 as a therapeutic target in BPD.

Newborn C57BL/6N mice were exposed to normoxia or 85% oxygen for 28 days. Animal growth and dynamic respiratory compliance were reduced in animals exposed to hyperoxia, paralleled by decreased septation, airspace enlargement, and increased septal wall thickness. Changes were evident after 14 days, and were more pronounced after 28 days of hyperoxic exposure. At the mRNA level PDEs 1A and 4A were up-regulated, while PDE5A was down-regulated under hyperoxia. Immunoblotting confirmed these trends in PDE4A and PDE5A at the protein expression level. Treatment with cilomilast (PDE4 inhibitor, 5 mg·kg^-1·day^-1) between days 14 and 28 significantly decreased the mean intra-alveolar distance, septal wall thickness and total airspace area, and improved dynamic lung compliance.

Pharmacological inhibition of PDE4 improved lung alveolarisation in hyperoxia-induced BPD, and may thus offer a new therapeutic modality in the clinical management of BPD.