Mechanisms of Hydrocortisone Regulation of the Perinatal Pulmonary Vasculature

Bronchopulmonary dysplasia (BPD) is a lung disease that affects many premature infants born at very low birth weight. BPD is a chronic disease that can lead to serious long-term health problems and increases the risk of mortality. One potential complication of BPD is the development of pulmonary hypertension (PH), further increasing morbidity and mortality. There are few well-studied therapies for infants with BPD-associated PH. Hydrocortisone is a steroid that has been used in neonatal intensive care unit for treatment of several diseases but has not been well-studied for use in neonatal PH. This project proposes to study the effects of hydrocortisone on neonatal lungs and pulmonary vasculature in a mouse model of BPD. Exposure of neonatal mice to high oxygen for the first 14 days of life leads to development of lung disease similar to BPD, development of PH, and abnormalities in the nitric oxide signaling pathways, including induction of phosphodiesterase-5 (PDE5), an enzyme implicated in development of PH. We have previously demonstrated that hydrocortisone attenuates evidence of PH and normalizes PDE5 activity in the murine model of hyperoxic lung injury. We hypothesize that hydrocortisone has direct effects on the pulmonary vasculature and that these effects are secondary to attenuation of PDE5 and decreased oxidative stress, including induction of extracellular superoxide dismutase (ecSOD), an important lung antioxidant. The results of this project will allow for future study of hydrocortisone as novel therapy for neonatal PH.