Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth affecting 30% of infants with birthweights < 1000 grams. Recently, pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) have been recognized as complications in approximately 25% of infants with moderate or severe BPD. Once infants develop PH, little is known about how to treat them, and risk of morbidity and mortality is very high. One of the mainstays of BPD therapy is oxygen (O2), but supraphysiologic O2 concentrations in combination with mechanical ventilation increase reactive oxygen species (ROS) production, inducing significant vascular dysfunction in neonates. Potential key targets for ROS-mediated dysregulation in the pulmonary vasculature are involved in cGMP signaling - soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). In the previous funding period, we utilized a mouse model of hyperoxia-induced lung disease and PH to demonstrate that hyperoxia-exposed mice develop significant pulmonary and vascular disease, characterized by alveolar simplification, fewer capillaries, small pulmonary arteries (PA) remodeling, and RVH. We demonstrated that hyperoxia rapidly decreased lung and PA soluble guanylate cyclase (sGC) expression and activity and increased lung and PA phosphodiesterase 5 (PDE5) activity, leading to disruption of cGMP-mediated downstream signaling. Giving low-dose sildenafil, a PDE5 inhibitor, concurrent with hyperoxia prevented increased PDE5 activity, vascular remodeling, and RVH, but was unable to restore normal capillary density and alveolarization. In preliminary data for this proposal, we have demonstrated that another environmental stressor, intrauterine growth restriction (IUGR) due to placental insufficiency, leads to a significant delay in alveolarization with decreased expression of a key lung growth factor, insulin-like growth factor-1 (IGF-1), decreased sGC expression and activity, and impaired alveolarization. IUGR mice have an exaggerated phenotype with hyperoxia vs. appropriately grown mice with further decreased sGC expression and activity and impaired alveolarization. We hypothesize that both growth restriction and hyperoxia-induced mitochondrial ROS disrupt the critical sGC-cGMP signaling pathway, leading to impaired alveolarization and angiogenesis. We will utilize our established mouse model of hyperoxia-induced lung injury in combination with a novel model of IUGR to elucidate the molecular mechanism by which ROS and growth restriction disrupt sGC-cGMP signaling and lung development. These studies will provide the pathophysiologic, mechanistic framework to improve pharmacologic treatment of BPD infants with PH. We believe sGC is a key integrator for multiple signals that impact alveolarization and angiogenesis in the neonatal period. sGC stimulators such as riocinguat are approved in adults with PH and represent a novel and potentially immediate therapeutic option for BPD-PH infants if a rationale for their use can be demonstrated.

Public Health Relevance

Pulmonary hypertension associated with bronchopulmonary dysplasia is a late complication of premature birth that results in significant long-term morbidity, increased health care costs and utilization, and in many cases, increased mortality. In this proposal, we will utilize a mouse model to determine how oxygen exposure and growth restriction negatively impact soluble guanylate cyclase-cGMP signaling in this condition and whether treatment with novel sGC stimulators such as riocinguat can prevent disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL109478-08
Application #
9533669
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Natarajan, Aruna R
Project Start
2011-06-15
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Gupta, Anita; Perez, Marta; Lee, Keng Jin et al. (2015) SOD2 activity is not impacted by hyperoxia in murine neonatal pulmonary artery smooth muscle cells and mice. Int J Mol Sci 16:6373-90
Heilman, Rachel P; Lagoski, Megan B; Lee, Keng Jin et al. (2015) Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice. Am J Physiol Heart Circ Physiol 308:H1575-82

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