Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia.
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. The aim of the present study was to investigate PDE expression in the lung of hyperoxia-exposed mice, and to 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, PDE1A and PDE4A were upregulated while PDE5A was downregulated 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 phosphodiesterase improved lung alveolarisation in hyperoxia-induced bronchopulmonary dysplasia, and thus may offer a new therapeutic modality in the clinical management of bronchopulmonary dysplasia.
Woyda
K
K
University of Giessen Lung Center, Germany.
Koebrich
S
S
Reiss
I
I
Rudloff
S
S
Pullamsetti
S S
SS
Rühlmann
A
A
Weissmann
N
N
Ghofrani
H A
HA
Günther
A
A
Seeger
W
W
Grimminger
F
F
Morty
R E
RE
Schermuly
R T
RT
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D018496:Hyperoxia / Q000201:enzymology*; D008170:Lung Compliance / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D010726:Phosphodiesterase Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4