Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia

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.The aim of the present study was to investigate PDE expression in the lung of hyperoxiaexposed 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) 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 hyperoxiainduced bronchopulmonary dysplasia, and thus may offer a new therapeutic modality in the clinical management of bronchopulmonary dysplasia.

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

“…The newborn mouse model of BPD used in this study, in which newborn mice are exposed to normoxic (21% O 2 ) or hyperoxic (85% O 2 ) gas mixtures for the first 28 days after birth, has been defined and characterized by others (14,18,19) and described previously by our own laboratory (20,21). Mice were killed at days 1, 7, 14, 21, and 28 after birth for analysis, which spans the period of late lung development in mice.…”

“…Mice were killed at days 1, 7, 14, 21, and 28 after birth for analysis, which spans the period of late lung development in mice. The processing of lung tissue from this model for RNA and protein analysis, as well as immunohistology, has been described previously (20,21), as has the inhibition of TGF-b signaling in mouse pup lungs with a TGF-b1,2,3-neutralizing IgG 1 antibody (1D11; Genzyme, Cambridge, MA) (22). In these studies, an isotype-matched nonimmune IgG 1 antibody (MOPC21; Sigma, St. Louis, MO) did not modulate pulmonary TGF-b signaling.…”

Inactivation of sestrin 2 induces TGF-β signaling and partially rescues pulmonary emphysema in a mouse model of COPD

“…For alveolar morphometry, lungs were fixed with 4.5% paraformaldehyde in PBS (pH 7.0) via the trachea at a pressure of 22 cm H 2 O, and the mean linear intercept and the airspace were assessed in lung sections stained with hematoxylin and eosin, as described previously (Woyda et al, 2009). …”

Wnt3a Mediates the Inhibitory Effect of Hyperoxia on the Transdifferentiation of AECIIs to AECIs

“…Advance in mechanical ventilation increases the percentage of infants surviving delivery earlier in gestation but also results in a high morbidity of BPD (Merritt et al 2009). In animal models, retarded lung alveolization and differentiation of alveolar epithelial type II cells (AECIIs), fewer and larger alveoli, and enlarged airspace area were found in hyperoxia-exposed lungs (Dauger et al 2003;Wang et al 2005;Woyda et al 2009). These damages were considered the result of the decreased proliferation of alveolar epithelium.…”

“…In animal models, retarded lung alveolization and differentiation of alveolar epithelial type II cells (AECIIs), fewer and larger alveoli, and enlarged airspace area were found in hyperoxia-exposed lungs (Dauger et al 2003;Wang et al 2005;Woyda et al 2009). These damages were considered the result of the decreased proliferation of alveolar epithelium.…”