Abstract/Summary: Bronchopulmonary dysplasia (BPD) is a chronic cardiopulmonary complication among survivors of preterm birth, with more than 10,000 new diagnoses in the US each year and healthcare costs estimated to exceed $2.5 billion. During my NHLBI K08, I have shown that pharmacologic inhibition or genetic deletion of the S- nitrosothiol catabolic enzyme, S-nitrosoglutathione reductase (GSNO reductase), prevents the development of all aspects of hyperoxic murine BPD including pulmonary vascular features. Moreover, increased airway GSNO reverses the BPD airway hyperreactivity and promotes bronchodilation in these mice. The GSNO- repleting agent, inhaled ethyl nitrite, has been used safely and successfully to treat pulmonary hypertension in mechanically ventilated human newborns. Here, I propose a pilot study using inhaled ethyl nitrite to treat hypoxic respiratory failure in human infants with BPD. Unlike inhaled nitric oxide (iNO), ethyl nitrite rapidly and robustly increases pulmonary GSNO levels in animal models, and should serve to reverse the bronchospasm and ventilation/perfusion mismatch that characterize BPD. I believe this preliminary study will be a particularly valuable clinical application of my K08 data, as other novel treatments for respiratory failure have not been developed for respiratory failure in BPD. As our primary clinical outcome variable, we will have power (>0.9) to detect a 41% (+ 27) improvement in pre/post oxygen saturation index with a 4 hour treatment of inhaled ethyl nitrite. We have a busy NICU at UH Rainbow Babies and Children's Hospital, with more than 25 infants/year with BPD that would be eligible for this two year pilot. We are also fortunate to have investigators on campus familiar with ethyl nitrite use in humans, Drs. James Reynolds and Jonathan Stamler. Of note, Dr. Stamler was the lead investigator in the initial neonatal ethyl nitrite study, published in The Lancet. My K08 mentor, Dr. Gaston, can perform the requisite GSNO airway assays in his laboratory, and has an FDA regulatory core and part 11-compliant DCC as part of his Program Project Grant that can assist with the IND and data management. The UH Clinical Research Center will provide FDA regulatory, research staffing, and coordinator cores to support this clinical trial. We therefore have an optimal situation for testing whether inhaled ethyl nitrite improves oxygen saturation index in infants with BPD who have respiratory failure. At the end of this proof of principle study, we hope to be able to apply these findings to an R01 or equivalent proposal to translate my K08 findings into a novel treatment strategy for BPD.