Abstract Introduction The “first 1,000 days”—9 antenatal months and first 2 years of life—underpin the developmental origins of lung health and disease. Lung function tracks along consistent percentiles from infancy, through childhood, and into adulthood. Former preterm infants with bronchopulmonary dysplasia (BPD) have lower baseline lung function in infancy, peak lung function, and threshold for development of symptomatic lung disease in adulthood. This lifelong lung dysfunction suggests a possible structural risk factor that is an unexplored link in these trajectories. Dysanapsis is the concept of disproportionately decreased airways growth compared to distal lung parenchyma, defined by a decreased ratio of forced expiratory volume over 1 second (FEV1) to forced vital capacity (FVC), with normal FEV1. We previously demonstrated dysanaptic lung growth via spirometry, decreased airways diameters, alveolar surface area, and parenchymal-airway attachments in 14-day-old rats in a preclinical model of inflammation-induced BPD. However, it remains unknown how spirometry evolves after antenatal inflammation and whether early dysanaptic growth affects long-term lung function in experimental BPD. Methods Fetal rats were exposed to intraamniotic endotoxin (ETX, 10 μg) at embryonic day 20 (E20), delivered at E22 (lung development equivalent to 26-28 weeks gestation human), and raised under normal conditions. At postnatal day 28 (D28; equivalent to 3-8-year-old human), lung function was measured via FlexiVent invasive ventilation utilizing single-frequency oscillations for basic mechanics and negative pressure forced expiration for spirometry. Data was compared to previously published data at D14 (equivalent to human infancy). Results Spirometry at D28 demonstrated decreases in FEV0.1, FEV0.1 /FVC, and forced expiratory flow at 50% vital capacity (FEF50) in ETX-exposed animals compared to controls (all p 0.01). This differed from D14 ETX-exposed pups that had decreased FEV0.1/FVC (p 0.05) with no difference in FEV0.1 compared to controls (Fig.1). D28 ETX-exposed pups had increased respiratory system resistance, increased Newtonian resistance, and decreased respiratory system compliance (all p 0.001 v. D28 controls). These functional changes persisted from D14; differences were sustained when correcting for length. Conclusion We found that a single antenatal ETX exposure causes sustained impairments of lung function at infancy (D14) persisting into childhood (D28). Given the changes in spirometry from D14 to D28, we speculate that early dysanapsis may predispose to structural obstructive lung disease and lead to an impaired lung function trajectory over the lifespan in infants with BPD. Our data adds to the growing body of evidence supporting perinatal events underpin developmental origins of lung disease. This abstract is funded by: R38 HL143511, T32 HL160508-03, K38 HL180910-01, K08 HL150333-01, R01 HL151630, R01 HD107700, R01 HL68702, R01 HL145679
Mcginn et al. (Fri,) studied this question.