Pulmonary vascular disease is evident in gene regulation of experimental bronchopulmonary dysplasia

Abstract

Objective: To examine the gene expression regarding pulmonary vascular disease in experimental bronchopulmonary dysplasia in young mice. Premature delivery puts babies at risk of severe complications. Bronchopulmonary dysplasia (BPD) is a common complication of premature birth leading to lifelong affection of pulmonary function. BPD is recognized as a disease of arrested alveolar development. The disease process is not fully described and no complete cure or prevention is known. The focus of interest in the search for treatment and prevention of BPD has traditionally been at airspace level; however, the pulmonary vasculature is increasingly acknowledged in the pathology of BPD. The aim of the investigation was to study the gene expression in lungs with BPD with regards to pulmonary vascular disease (PVD).

Methods: We employed a murine model of hyperoxia-induced BPD and gene expression microarray technique to determine the mRNA expression in lung tissue from young mice. We combined gene expression pathway analysis and analyzed the biological function of multiple single gene transcripts from lung homogenate to study the PVD relevant gene expression.

Results: There were n = 117 significantly differentially regulated genes related to PVD through down-regulation of contractile elements, up- and down-regulation of factors involved in vascular tone and tissue-specific genes. Several genes also allowed for pinpointing gene expression differences to the pulmonary vasculature. The gene Nppa coding for a natriuretic peptide, a potent vasodilator, was significantly down-regulated and there was a significant up-regulation of Pde1a (phosphodiesterase 1A), Ptger3 (prostaglandin e receptor 3), and Ptgs1 (prostaglandin-endoperoxide synthase one).

Conclusion: The pulmonary vasculature is affected by the arrest of secondary alveolarization as seen by differentially regulated genes involved in vascular tone and pulmonary vasculature suggesting BPD is not purely an airspace disease. Clues to prevention and treatment may lie in the pulmonary vascular system.

Keywords:

• Bronchopulmonary dysplasia
• gene regulation
• pulmonary hypertension
• pulmonary vascular disease
• vascular tone

Acknowledgements

We thank Professor Helge Scott and the Institute of Clinical Medicine, Department of Pathology, University of Oslo, for support and knowledge regarding the histological preparations of lungs and for valuable help with microscopy and methodology for determining Mean Linear Intercepts (MLI), Ståle Nygård, Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, for normalizing raw data, Marit Holden, for input on statistical presentation of results. We greatly appreciate all the assistance from the staff at Center of Comparative Medicine, Oslo University Hospital; Rikshospitalet where the animal experiments took place. Monica Atneosen-Åsegg, Pediatric Research Institute, the University of Oslo for guiding the first author through PCR validation calculations and support with laboratory work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The research leading to these results has received funding from the Polish - Norwegian Research Programme operated by the National Centre for Research and Development under the Norwegian Financial Mechanism 2009–2014 in the frame of Project Contract No Pol-Nor/196065/54/2013. The study was supported by EEA grants: grant number: PL12-0036. Helse Sør-Øst, Norway has contributed to parts of the salary for the first author.