Mechanisms of Hydrocortisone Regulation of the Perinatal Pulmonary Vasculature

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Bronchopulmonary dysplasia (BPD) affects 10,000 premature infants annually with an estimated cost of $2.4 billion. Up to a third of infants with BPD go on to develop pulmonary hypertension (PH), leading to worse long-term outcomes and increased mortality. Thus far, no effective therapies have been identified for BPD- associated PH. However, data from animal models suggest that phosphodiesterase-5 (PDE5) and extracellular superoxide dismutase (ecSOD) may hold promise as therapeutic targets in PH. PDE5 contributes to vasoconstriction by catabolizing cyclic guanosine monophosphate (cGMP), a critical pulmonary vasodilator. We have previously demonstrated that oxidative stress, a key mediator in the mouse model of hyperoxic lung injury, activates PDE5 and leads to pulmonary vascular remodeling. Overexpression of the antioxidant ecSOD has been shown to protect the lung against hyperoxia in the newborn mouse. Our published and preliminary data in the mouse model of hyperoxic lung injury demonstrates that hydrocortisone, a glucocorticoid with a known safety profile in premature infants, normalizes hyperoxia-induced PDE5 activation and increases ecSOD protein in vitro, and decreases right ventricular hypertrophy in vivo. We believe that hydrocortisone has a direct effect on the pulmonary vasculature and thus represents a novel treatment for neonatal pulmonary hypertension. Our central hypothesis is that HC reverses hyperoxia- induced changes in the pulmonary vasculature through attenuation of aberrant PDE5 activity and oxidative stress via upregulation of ecSOD. We will utilize isolated mouse pulmonary artery smooth muscle cells, the murine model of hyperoxia-induced lung injury, and ecSOD knockout mice to characterize the direct effects of hydrocortisone on pulmonary vasculature and on vascular signaling pathways. These findings will lay the foundation for the use of hydrocortisone as novel therapy in pulmonary hypertension, and add new knowledge about the role of PDE5 and ecSOD in pathophysiology and treatment of BPD-associated PH. The candidate’s long-term career goal is to become an independently funded researcher with expertise in glucocorticoid signaling and pulmonary vascular pathophysiology. The short-term goal during the award period is to elucidate the specific pathways and mechanisms by which glucocorticoids affect neonatal pulmonary vasculature. The candidate’s career development plan involves didactic and skill acquisition training, career development activities, and a mentored research experience. This innovative work will be mentored by Dr. Kathryn Farrow, an expert in pulmonary vascular biology and nitric oxide signaling pathways in the pulmonary vasculature, with additional guidance of a highly experienced advisory team. This work is complimented by the academic environment at Northwestern University, the strength of the pulmonary research being conducted in the Department of Pediatrics, and the commitment of the Division of Neonatology and the Department of Pediatrics to the support and development of junior clinician scientists.