Early dysanapsis in experimental bronchopulmonary dysplasia: implications for lifelong lung disease

Disruptions during perinatal fetal lung development can lead to postnatal chronic lung diseases such as bronchopulmonary dysplasia (BPD). Along with decreased alveolar and pulmonary vascular growth, abnormal airway growth occurs in BPD. Previous studies in rats have shown that antenatal endotoxin (AN-ETX) mimicking maternal chorioamnionitis causes dysanapsis during the neonatal period. Whether dysanaptic growth alters long-term lung function remains unknown. We hypothesized that antenatal endotoxin causes persistent differences between airway and distal lung growth with age in experimental BPD. Sprague-Dawley rats were exposed to AN-ETX at embryonic day 20 (E20) by intraamniotic injection and delivered on E22, analogous to human preterm 26-28 wk gestation. Pups raised via naive foster dams were evaluated for BPD-associated parameters on postnatal days 14 (D14) and 28 (D28), akin to infancy and childhood human lung development. Lung histologic morphometry, lung mechanics testing, and airway and pulmonary vasculature microcomputed tomography (µCT) evaluations were performed to assess growth at D14 and D28. AN-ETX-exposed rats demonstrated persistent somatic growth failure, decreased alveolarization, decreased vascularization, right ventricular hypertrophy, and impaired lung mechanics at both D14 and D28. AN-ETX exposure decreased large airway size at D14, but also medium airway diameters by D28. AN-ETX exposure caused early airflow obstruction at D14 [decreased forced expiratory volume over 0.1 s to forced vital capacity (FEV_0.1/FVC) ratio], which worsened by D28 (decreased FEV_0.1 and FEV_0.1/FVC ratio). Adverse antenatal stress alone is sufficient to cause sustained abnormalities of lung development beyond the neonatal period. Early dysanapsis may predispose to structural obstructive disease and impair lung function over the lifespan.NEW & NOTEWORTHY Disruptions during perinatal lung development can lead to chronic lung diseases such as bronchopulmonary dysplasia (BPD). Rats exposed to a single intraamniotic endotoxin injection were evaluated for BPD-associated parameters of lung structure and function on postnatal days 14 and 28, akin to human infancy and childhood. Endotoxin-exposed rats demonstrated persistent impairments in lung development and function. This is the first preclinical study to suggest that early dysanaptic growth may predispose to lifelong impaired lung function.