Aberrant cGMP signaling persists during recovery in mice with oxygen-induced pulmonary hypertension

• Published in: PloS one 2017-08, Vol.12 (8), p.e0180957-e0180957
• Main Authors: Perez, Marta, Lee, Keng Jin, Cardona, Herminio J, Taylor, Joann M, Robbins, Mary E, Waypa, Gregory B, Berkelhamer, Sara K, Farrow, Kathryn N
• Format: Article
• Language: English
• Subjects: Aberration; Alveoli; Animals; Animals, Newborn; Biology and Life Sciences; Birth; Bronchopulmonary dysplasia; Bronchopulmonary Dysplasia - pathology; Critical care; Cyclic GMP; Cyclic GMP - metabolism; Cyclic guanosine monophosphate; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Density; Disease Models, Animal; Dysplasia; Exposure; Genetic aspects; Guanosine; Guanylate cyclase; Guanylate Cyclase - metabolism; Hyperoxia; Hyperoxia - pathology; Hypertension; Hypertension, Pulmonary - pathology; Hypertrophy, Right Ventricular - pathology; Hypoxia; Infants; Lung - pathology; Lung diseases; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Neonates; Newborn babies; Nitric oxide; Ostomy; Oxygen; Oxygen - metabolism; Pediatrics; Phosphodiesterase; Phosphodiesterase 5 Inhibitors - pharmacology; Physical Sciences; Physiology; Premature birth; Pulmonary Alveoli - physiology; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - physiology; Pulmonary hypertension; Recovery; Recovery (Medical); Research and Analysis Methods; Risk factors; Rodents; Signal Transduction; Sildenafil; Sildenafil Citrate - pharmacology; Simplification; Vascular Remodeling; Wall thickness
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0180957

Bronchopulmonary dysplasia (BPD), a common complication of preterm birth, is associated with pulmonary hypertension (PH) in 25% of infants with moderate to severe BPD. Neonatal mice exposed to hyperoxia for 14d develop lung disease similar to BPD, with evidence of associated PH. The cyclic guanosine monophosphate (cGMP) signaling pathway has not been well studied in BPD-associated PH. In addition, there is little data about the natural history of hyperoxia-induced PH in mice or the utility of phosphodiesterase-5 (PDE5) inhibition in established disease. C57BL/6 mice were placed in room air or 75% O2 within 24h of birth for 14d, followed by recovery in room air for an additional 7 days (21d). Additional pups were treated with either vehicle or sildenafil for 7d during room air recovery. Mean alveolar area, pulmonary artery (PA) medial wall thickness (MWT), RVH, and vessel density were evaluated at 21d. PA protein from 21d animals was analyzed for soluble guanylate cyclase (sGC) activity, PDE5 activity, and cGMP levels. Neonatal hyperoxia exposure results in persistent alveolar simplification, RVH, decreased vessel density, increased MWT, and disrupted cGMP signaling despite a period of room air recovery. Delayed treatment with sildenafil during room air recovery is associated with improved RVH and decreased PA PDE5 activity, but does not have significant effects on alveolar simplification, PA remodeling, or vessel density. These data are consistent with clinical studies suggesting inconsistent effects of sildenafil treatment in infants with BPD-associated PH.