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

Date Published: August 9, 2017

Publisher: Public Library of Science

Author(s): Marta Perez, Keng Jin Lee, Herminio J. Cardona, Joann M. Taylor, Mary E. Robbins, Gregory B. Waypa, Sara K. Berkelhamer, Kathryn N. Farrow, You-Yang Zhao.


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.

Partial Text

Bronchopulmonary dysplasia (BPD) remains a significant contributor to late morbidity and mortality of formerly premature infants [1]. A subset of infants with BPD will go on to develop pulmonary hypertension (PH), which can result in right ventricular hypertrophy (RVH) and right ventricular failure. Not surprisingly, development of PH is associated with longer length of hospitalization and increased healthcare costs [2–5]. In addition, recent reports indicate that mortality from BPD-associated PH is as high as 50% by 2 years [3]. Despite significant advances in neonatal critical care, the best treatment options for BPD infants with PH have not been defined. Furthermore, the underlying mechanisms and signaling pathways involved in the development of BPD-associated PH remain poorly understood.

Given the paucity of available treatment options, oxygen therapy remains the cornerstone of BPD treatment. Yet, there is increasing evidence from animal models that neonatal hyperoxia exposure disrupts pulmonary alveolar and vascular development resulting in long-term dysfunction [7–9, 24–28]. Neonatal mice exposed to prolonged hyperoxia develop BPD-like lung injury characterized by alveolar simplification, cardiovascular remodeling, and aberrant cGMP signaling [6]. While it is apparent that even short exposures to oxygen during the neonatal period can lead to persistent injury in rodents [6, 9, 10, 29], it is not clear how long such injury lasts and if recovery can be accelerated through the use of targeted pharmacological treatment. In the present study, we wanted to determine whether the cardiopulmonary and signaling anomalies associated with neonatal hyperoxia exposure persist even after a period of room air recovery. We demonstrate that exposure of neonatal mice to high levels of oxygen during the first two weeks of life leads to persistent pulmonary and cardiovascular anomalies as well as disruptions in pulmonary vascular NO-cGMP signaling that are still apparent at one month of life. This is consistent with other recent studies suggesting that hyperoxia-mediated lung and cardiovascular injury can last up to 8 weeks of age in mice [8, 26–28]. However, to date, no one has investigated potential therapeutic options in established disease, which is where data is desperately needed clinically. In the present study, we show that treatment with low dose sildenafil, a PDE5 inhibitor, during the first week of room air recovery, is associated with more rapid improvement in RVH and decreases in vascular PDE5 activity. However, sildenafil does not improve the rate of lung repair and recovery.




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