Defective fibroblast growth factor signaling allows for nonbranching growth of the respiratory-derived fistula tract in esophageal atresia with tracheoesophageal fistula

• Published in: Journal of pediatric surgery Vol. 35; no. 10; pp. 1421 - 1425
• Main Authors: Crisera, Christopher A., Maldonado, Thomas S., Longaker, Michael T., Gittes, George K.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier Inc 01.10.2000; Elsevier
• Subjects: Animals; Biological and medical sciences; Down-Regulation - physiology; Esophageal atresia; Esophageal Atresia - complications; Esophageal Atresia - embryology; Esophageal Atresia - metabolism; Esophagus; Female; fibroblast growth factor receptors; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fluorescent Antibody Technique; Gastroenterology. Liver. Pancreas. Abdomen; Lung - embryology; Lung - growth & development; Lung - metabolism; Malformations; Medical sciences; Mesoderm - cytology; Mesoderm - metabolism; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Fibroblast Growth Factor - metabolism; Respiratory Mucosa - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction - physiology; tracheoesophageal fistula; Tracheoesophageal Fistula - complications; Tracheoesophageal Fistula - embryology; Tracheoesophageal Fistula - metabolism; Esophageal atresia; fibroblast growth factor receptors; tracheoesophageal fistula; Fibroblast growth factor; Molecular form; Tracheoesophageal; Rat; Pathogenesis; Esophageal disease; Fistula; Atresia; Complication; Fetus; Diseases of the trachea; Respiratory disease; Deficiency; Cytokine; Rodentia; Congenital disease; Esophagus; Vertebrata; Experimental disease; Growth factor receptor; Mammalia; Malformation; Polypeptide; Animal; Digestive diseases; Growth factor
• ISSN: 0022-3468; 1531-5037
• DOI: 10.1053/jpsu.2000.16404

Background/Purpose: The fistula tract in esophageal atresia with tracheoesophageal fistula (EA-TEF) appears to arise from a trifurcation of the embryonic lung bud. Subsequently, it does not branch like the other bronchi, which also arise from the lung bud. Previous results have implied that aberrant mesenchymal-epithelial signaling in the developing foregut, possibly involving fibroblast growth factors, may allow for the nonbranching growth of the fistula, and the ultimate development of the fistula tract in TEF. Methods: Adriamycin injections into pregnant rat dams induced EA-TEF formation in rat embryos. Control and Adriamycin-exposed embryos were harvested on the 13th gestational day, and the developing foregut was isolated with microdissection. mRNA was isolated from the developing fistula tract, embryonic lung, and normal embryonic esophagus. Reverse transcription-polymerase chain reaction (RT-PCR) for the IIIb splice variant of the FGF2R receptor was performed. Foregut specimens also were processed for histologic analysis, and immunofluorescence for FGF1 was performed. Results: FGF2R-IIIb is specifically absent from the developing fistula tract in TEF, whereas it is present in the normal developing lung and esophagus. FGF1 also is uniquely absent from the developing fistula tract, but it is present in the normal lung mesenchyme. Conclusions: FGF1, FGF7, and FGF10 are critical mesenchymal factors that mediate proliferation and branching morphogenesis by the developing respiratory epithelium. The absence of FGF2R-IIIb, the obligate common receptor for FGF7 and FGF10, from the fistula tract, and the absence of FGF1 in the fistula tract mesenchyme, collectively imply the absence of a specific FGF signaling pathway in the developing fistula tract. This absence of FGF signaling could explain the lack of branching by the developing fistula tract as it grows caudally in the abnormally developing embryo. Downregulation of these components of the FGF signaling pathways may allow for a patterned compensation by the embryo for the proximal foregut atresia in this anomaly. This compensation may then reestablish gastrointestinal continuity as the fistula tract connects to the developing stomach. J Pediatr Surg 35:1421-1425. Copyright © 2000 by W.B. Saunders Company.