Lung hypoplasia in rats with esophageal atresia and tracheo–esophageal fistula

Abstract

IntroductIon: survivors of esophageal atresia and tracheo-esophageal fistula (ea-TeF) often suffer chronic respiratory tract disease. ea-TeF results from abnormal emergence of the trachea from the foregut. This study in a rat model tests the hypothesis that primary lung maldevelopment might be a downstream consequence of this defect. results: The lung was hypoplastic in rats with ea-TeF although the histological pattern was normal. Maturation and arteriolar wall thickness were unchanged, but mesenchymal control of airway branching was weakened. This branching was deficient from embryonal day (e13) on in adriamycin-treated explants. dIscussIon: In conclusion, the lungs were hypoplastic in rats with experimental ea-TeF due to defective embryonal airway branching. however, arteriolar wall and respiratory epithelial patterns remained normal. These findings suggest that similarly defective lung development might contribute to chronic respiratory disease in ea-TeF patients. Methods: Pregnant rats received either 1.75 mg/kg i.p. adriamycin or vehicle on e7, e8, and e9. Lungs were recovered at e15, e18, and e2. Lung weight/body weight ratio, total DNa and protein, radial alveolar count, arteriolar wall thickness, lung maturity, and mesenchymal control of airway branching were assessed. e13 lungs were cultured for 72 h and explant airway branching was measured daily. For comparisons, nonparametric tests (*P < 0.05) were used.

Adriamycin-Induced Models of VACTERL Association

“…In the trachea, malformed and deficient cartilage has been described, and correlation of these findings with the high rate of tracheomalacia afflicting neonates with OA/TOF was intimated Pole et al, 2001]. The lungs of treated embryos were hypoplastic and had decreased airway branching; however, histological findings were similar to controls [Xiaomei et al, 2012]. Other tracheo-oesophageal anomalies including foregut duplications and bronchopulmonary foregut malformations, such as an ectopic lung or bronchus arising from the oesophagus, are reported in the model, indicating these may have a similar developmental aetiology to OA/TOF in the ARM [Qi and Beasley, 1999b;Qi et al, 2001].…”

“…Between 28% and 93% of ARM embryos have tracheooesophageal malformations [Diez-Pardo et al, 1996;Merei et al, 1997b;Qi et al, 2001;Gillick et al, 2003;Xiaomei et al, 2012]. A spectrum of these anomalies have been described in the ARM, the near-term embryo most frequently (80%) displaying an upper OA pouch with distal TOF .…”

“…Respiratory tissues exhibit specialised properties including branching morphogenesis [Hogan et al, 1997]. In the ARM, the fistula is not normally seen to branch in vivo, but it can be induced to branch when cultured in normal or respiratory mesen- chyme and in response to fibroblast growth factors [Crisera et al, 2000c;Spilde et al, 2004;Xiaomei et al, 2012]. The evidence to date suggests that the fistula may arise from a bi-potential origin which can be induced under certain conditions to establish a respiratory identity when exposed to the appropriate mesenchymal signals.…”

Abnormal Sonic hedgehog signaling in the lung of rats with esophageal atresia induced by adriamycin

“…It was recently reported that rat fetuses with esophageal atresia and tracheoesophageal fistula induced by adriamycin have hypoplastic lungs and abnormal control of branching with FGF10 (fibroblast growth factor 10) overexpression in the pseudoglandular, canalicular, and saccular stage of lung development (22,23).…”

“…Adriamycin-induced EA-TEF is associated with defective tracheobronchial branching and some degree of lung hypoplasia (22,23). The present study examined whether the abnormal foregut expression pattern of Shh at the site of emergence of the tracheobronchial bud is translated into the developing lung of rats with EA-TEF/VACTERL association.…”