Preterm delivery at less than 37 weeks of gestation is the most common cause of abnormal lung development and one with potential lifelong sequelae since preterm delivery can limit the ability of the lung to reach its maximum potential. The survival of extremely premature infants (24-28 wks gestation), who frequently develop bronchopulmonary dysplasia (BPD), has shifted focus away from moderate and late premature (MLP) infants (? 30 to < 37 wks gestation), who initially require relatively little respiratory support and rarely develop BPD. However, MLP infants are the majority of premature births and develop a high incidence of wheezy respiratory illnesses, hospitalizations, and use of asthma medications compared to infants delivered at term gestation. Therefore, MLP infants contribute to high morbidity, family stress, and health care costs following NICU discharge. Pulmonary function testing of MLP infants show they exhibit reduced expiratory flows compared to age-matched term infants and do not demonstrate catch-up when tested in later life. Continuous positive airway pressure (CPAP), which provides mechanical lung distention, is a standard of NICU care for maintaining functional residual capacity (FRC), avoiding intubation and barotrauma, and decreasing respiratory morbidity. While CPAP is currently used to minimize lung injury, it may also promote lung growth and development, since mechanical stretch of the lung is an important stimulus to lung growth. Supporting this, in studies in ferrets, we have demonstrated that 1-week of CPAP increased lung volume and airway size. In addition, we demonstrated that treatment of adult asthmatics with nocturnal CPAP for 1-week suppressed airway hyper-reactivity, an airway characteristic that is often present in subjects born prematurely. Lastly, we have found that among infants born prematurely (mean 32 weeks gestation) and who didn't develop BPD, those treated with CPAP in the NICU had larger lung volumes and greater pulmonary diffusion capacity compared to non-CPAP treated infants. We therefore hypothesize that CPAP stimulates lung growth, improves lung function, and suppresses airway hyper-reactivity in premature infants. We propose to test this hypothesis in a highly-translatable, non-human primate model in which moderately premature (140 days gestation, = 85% of 165 days term gestation) rhesus monkeys will be treated with 10 days CPAP (5 cmH2O) or sham CPAP (0 cmH2O). Pulmonary function and structure will be examined after the 10 days of CPAP and at 6 months of age. In addition we will determine underlying mechanism of CPAP action by examining mechano-sensitive pathways as well as determining if there are epigenetic modifications that may underlie the life-long effects of pre-term birth on lung function. Findings from this proposed study could directly support clinical trials to change the application of CPAP from that of respiratory support in the NICU to that of a therapeutic intervention to prevent altered lung development even in infants delivered as moderate or late preterm without clinical signs of respiratory distress after delivery.
Moderate to late premature infants (? 30 weeks, < 37 weeks) represent 70% of all preterm births and exhibit decreased pulmonary function at birth that fails to catch up with term birth children. These infants also show increased asthma and hospitalizations compared to full term infants. The purpose of this application is to determine if routine use of CPAP (continuous positive airway pressure) in these infants will stimulate lung growth to allow catch-up with term infants and prevent increased respiratory disease.
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