Bronchopulmonary dysplasia (BPD) is a common comorbid lung disease in extremely low birth weight (ELBW) infants accounting for significant morbidity, mortality and health care costs. There are currently few biomarkers that predict BPD and limited therapies that can prevent BPD development. This study will test the novel hypothesis that lower oral nitrate reductase (NR) activity, measured weeks before disease diagnosis, predicts the development of BPD in ELBW infants. Symbiotic bacteria residing on the distal tongue expressing NR, can reduce salivary nitrate to nitrite, which can then be further reduced to NO in systemic tissues. Oral NR activity has emerged as a critical modulator of systemic NO bioavailability and cardiopulmonary homeostasis in adults, however, the physiologic relevance of this pathway in infants remains unclear. In a preliminary study (N=28), we measured oral NR activity in ELBW infants, between 24 and 34 weeks' post-menstrual age (PMA) and unexpectedly observed that activity peaked 29 weeks' PMA. Further analyses revealed that this increase did not occur in infants subsequently diagnosed with BPD at 36 weeks' PMA. These data suggest that oral NR activity, measured weeks prior to diagnosis, may provide a novel test for identifying infants at risk for BPD development and the foundation for the hypothesis that oral NR activity will be lower in preterm infants that develop BPD compared to infants that do not develop lung disease. We propose a single-center prospective study design in which serial tongue swabs will be collected to assess NR activity, serum and urine nitrate and nitrite, and microbiome diversity. The latter will determine how changes in the oral microbiome relate to NR activity and may further predict BPD development. Differences between these parameters in infants who go on to develop BPD compared to those who do not will be integrated into predictive algorithms for BPD. Based on power analyses using preliminary data, we anticipate enrolling 221 infants born at <29 weeks' PMA. We propose the following aims: SA1- Determine if infants who develop BPD exhibit lower nitrate reductase activity compared to infants without BPD; SA2- Determine which bacteria significantly contribute to changes in NR activity and SA3-Develop a prediction model for BPD using nitrate reductase and/or other elements of nitrate metabolism. We anticipate that data derived from this proposal will identify a novel predictive biomarker for BPD that can be measured weeks prior to BPD and by non-invasive methods. Additionally, these studies may provide targets for development of novel therapeutics to prevent BPD in premature infants.
Extremely premature infants are at a high risk for death. Bronchopulmonary dysplasia remains a significant contributor to neonatal death, however, lacks a reliable predictive marker. In this proposal, we will test whether measurement of oral nitrate-reductase activity enables disease prediction thereby offering earlier risk identification and new opportunities for intervention to prevent infant death.
