Pathohistological study of adriamycin-induced tracheal agenesis in the fetal rat

Abstract

There have been few studies of tracheal agenesis (TA) because it is an extremely rare condition and is invariably fatal. However, it is recognised to be associated with a variety of oesophageal abnormalities, including oesophageal atresia (OA) and communicating bronchopulmonary foregut malformations (CBPFM). Except for some gross pathological reports, there has been no detailed histological investigation of this congenital abnormality. Adriamycin-induced TA in fetal rats provides a means of studying this uncommon condition, including its relationship to oesophageal abnormalities. TA was induced in rat features by intra-peritoneal injection of adriamycin (2 mg/kg) into timed-pregnant rats on days 6-9. Their 33 fetuses were removed by caesarean section, cut transversely, and stained after which the slides were examined. OA developed in 27/33 adriamycin-treated fetuses, TA occurred in 5. Four had type III while the 5th had type II TA. The oesophagus of fetuses with TA acquired tracheal features in the region where both ectopic bronchi originated. Two fetuses with TA also had OA, and 4 had a CBPFM. Other abnormalities detected involved the gastrointestinal, urinary and cardiovascular systems. The association of TA and oesophageal abnormalities suggests that there may be a spectrum of abnormalities comprising a number of variants, which may have a common aetiology. The other abnormalities co-existing in this animal model mirror those found in reported cases of human TA. Ultimately, the rat model of OA and TA may give insight into the embryogenesis of these malformations.

Adriamycin mouse model: a variable but reproducible model of tracheo-oesophageal malformations

“…The mean number of fetus developing oesophageal atresia are higher than those seen in this study, but this ranges from 41 to 85% between studies using a dose of 2 mg/kg on days 6-9 [6,7]. Tracheal agenesis is generally reported to occur rarely in the ARM [8] however, in one study 41% of the fetuses had tracheal agenesis [9]. Laryngotracheo-oesophageal clefts have not been found to occur in the ARM.…”

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

“…These observations demonstrated that patients with EA-TEF can have abnormal lung structure, particularly when they have associated malformations, and this could account for respiratory morbidity. The use of a pharmacologic rodent model for these investigations seems largely justified as all features of VACTERL association are strikingly reproduced: laryngo-tracheal ring anomalies leading to stenosis and tracheomalacia are similar in rats and infants with EA-TEF (41)(42)(43), and the entire spectrum of communicating or noncommunicating foregut malformations seen in infants (sequestrations, cysts, duplications) is reproduced in rats (44)(45)(46)(47). If the embryologic mechanisms of EA-TEF in infants and rats are similar and the malformations observed in the respiratory tract are identical, it is likely that failures of parenchymal development are also of the same nature in both settings.…”

A Large Animal Model of the Fetal Tracheal Stenosis/Atresia Spectrum

“…Such models have involved the prenatal delivery of different drugs (adriamycin, doxorubicin, or nitrofen), or genetic manipulations (sonic hedgehog and Bmp pathways, or FGF 18 expression) [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. These models have been instrumental in the elucidation of some of the mechanisms behind airway organogenesis and select disruptions thereof.…”