Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth affecting 30% of infants with birthweights <1000 grams. Recently, pulmonary hypertension (PH) and right-sided heart failure have been recognized as complications in infants with moderate or severe BPD. While the true prevalence remains unknown, one case series estimates that PH occurs in up to 25% of BPD infants. 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 soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). We have previously demonstrated that hyperoxia exposure leads to increased PDE5 expression and activity with concomitant decreased cGMP, and we have preliminary data that hyperoxia exposure decreases sGC expression and activity. Thus, if neonates are born prematurely and exposed to mechanical ventilation with supraphysiologic O2, then both sGC and PDE5 are vulnerable to dysregulation that can impact pulmonary vasoreactivity and vascular remodeling, leading to right ventricular hypertrophy over time. Our group has previously published that hyperoxia exposure increases both mitochondrial and cytoplasmic ROS in isolated pulmonary artery smooth muscle cells (PASMC). Mitochondrially-targeted antioxidants are sufficient to decrease PDE5 activity and restore normal cGMP levels in isolated PASMC. Additionally, in unpublished data, protein kinase G I1 (PKGI1) inhibitors are sufficient to block ROS-mediated increases in PDE5 and restore normal cGMP levels. We hypothesize that preterm birth combined with exposure to hyperoxia-induced mitochondrial ROS disrupts the critical sGC-cGMP-PKG-PDE5 signaling pathway within the lung, leading to abnormal pulmonary vascular growth and RVH as seen in infants with BPD and pulmonary hypertension. We will utilize the established mouse model of BPD in combination with novel techniques including neonatal mouse PASMC, neonatal living lung slices, and ratiometric redox sensors, to elucidate the molecular mechanism by which ROS disrupts this pathway. Furthermore, we will utilize the BPD mouse model to test whether antioxidants or sildenafil, a PDE5 inhibitor, are sufficient to either prevent PH if given concurrently with oxygen exposure or to reverse established PH if given during the convalescent phase. These studies will provide the pathophysiologic, mechanistic framework for future pre-clinical and clinical studies to improve prevention and pharmacologic treatment of BPD infants with PH. PDE5 inhibitors, such as sildenafil, are clinically available, and pharmacokinetic data are available for term neonates. They represent the most immediate therapeutic option for these 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 negatively impacts soluble guanylate cyclase-cGMP-phosphodiesterase-5 signaling in this condition and whether treatment with antioxidants or sildenafil, a phosphodiesterase-5 inhibitor, can reverse established disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL109478-02
Application #
8279185
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Lin, Sara
Project Start
2011-06-15
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$410,240
Indirect Cost
$94,196
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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