Supplemental O2 is among the most common treatments employed in neonatal intensive care units, particularly in the care of preterm and very low birth weight infants. Attempts are made to minimize O2 exposures, however, since hyperoxia may contribute to pathologies such as bronchopulmonary dysplasia, retinopathy of prematurity, and cerebral palsy. Despite these efforts, infants routinely experience episodes of hyperoxia during O2 therapy. Previous studies have shown that sustained exposures to hyperoxia have profound effects on respiratory control in developing mammals (smaller carotid bodies, reduced carotid body chemosensitivity, and attenuated hypoxic ventilatory responses (HVR)), but it is not known whether clinically relevant intermittent hyperoxia exposures elicit similar plasticity. Therefore, the primary objectives of the proposed research are to use a model of intermittent hyperoxia to study potential risks of O2 therapy to the developing respiratory control system and to explore mechanisms underlying any observed plasticity.
Specific Aim 1 will test the hypothesis that chronic intermittent hyperoxia impairs the morphological and functional development of the carotid body, thereby diminishing normoxic and hypoxic ventilation. Guided by published records of O2 exposures in preterm infants, neonatal rats will be exposed to intermittent hyperoxia profiles (varying levels of O2 and/or CO2) for the first two postnatal weeks. Following these exposures, carotid body morphology, single-unit carotid chemoafferent responses to hypoxia, and ventilation will be assessed. The time course and developmental specificity of the observed plasticity will also be determined.
Specific Aim 2 will test the hypothesis that chronic intermittent hyperoxia alters carotid body development through an activity- dependent mechanism that diminishes BDNF expression. Specifically, the effects of chronic intermittent hyperoxia on carotid body BDNF expression will be studied, and pharmacologic approaches will be used to manipulate BDNF signaling and carotid body activity to probe their roles in hyperoxia-induced plasticity. The proposed research is novel in focusing on developmental intermittent hyperoxia. The impact of chronic intermittent hyperoxia on respiratory control is virtually unknown despite the prevalence of hyperoxia in preterm infants and despite widespread recognition that other abnormal O2 exposures (e.g., sustained and intermittent hypoxia) have profound consequences for cardiorespiratory development. Thus, this model may have great significance for preterm infants exposed to periodic hyperoxia in the neonatal intensive care unit. If intermittent hyperoxia has adverse consequences for respiratory control, the model developed during this project period could be used to refine clinical practices and to explore preventative measures and therapies to improve patient outcomes. Undergraduate students will contribute to all aspects of the proposed research. Therefore, this project will also provide valuable training opportunities for talented students interested in biomedical research and medicine.
Supplemental oxygen is among the most common therapies used for preterm and low birth weight infants, and the rate of preterm births in the United States has risen over the past three decades to >12%. The proposed research will investigate whether intermittent exposure to abnormally high blood oxygen levels (hyperoxia), as routinely occurs during oxygen therapy, disrupts the normal development of the respiratory control system in an animal model. If changes in breathing are confirmed, this finding would raise concerns that oxygen therapy can increase the risk for breathing disorders and sudden infant death in human infants and may help to refine clinical practices.