Thyroid transcription factor-1 expression during normal human lung development and in patients with congenital diaphragmatic hernia.
OBJECTIVE
Thyroid transcription factor-1 (TTF-1) was detected in human respiratory epithelial cells from 11 weeks of gestation. TTF-1 is involved in both lung morphogenesis and in the regulation of surfactant proteins. Recently, low expression of TTF-1 in the nitrofen rat model of congenital diaphragmatic hernia (CDH) was shown and restoration of this downregulation by antenatal glucocorticolds (CS) was reported. The aim of this study was to investigate the expression of TTF-1 as a marker of lung morphogenesis in normal human lung development and in age-matched controls of human lung specimen in hypoplastic lungs of human CDH and other forms of lung hypoplasia.


METHODS
Immunohistochemistry by a monoclonal TTF-1 antibody was performed on paraffin sections of human fetal and neonatal lung tissues. The so-called developmental group (12 weeks' gestation to full term) included 47 lung specimens. The congenital hypoplasia group included 8 full-term CDH patients who died within 12 hours after birth, 3 full-term CDH patients who had antenatal CS therapy, and 4 full-term CDH patients after extracorporeal membrane oxygenation (ECMO) therapy. For comparison, 6 full-term born patients, who died of other forms of pulmonary hypoplasia, were used as comparative specimen. Immunohistochemical localization of TTF-1 was evaluated by light microscopy for 3 different areas of the airways including intrapulmonary bronchi, intermediate airways so-called terminal bronchioles, distal airways, and later sacculi and alveoli.


RESULTS
Nuclear TTF-1 staining was observed in the progenitor cells of the developing bronchiolar cells early in the human lung developmental series. At full term, TTF-1 was expressed in both type II epithelial cells and in subsets of respiratory nonciliated bronchiolar epithelial cells in a pattern similar in all studied groups. No TTF-1 expression was detected at the level of the intrapulmonary bronchi.


CONCLUSIONS
No difference in TTF-1 expression was observed in the developing early fetal and full-term neither in hypoplastic human lungs. This expression did not change with antenatal CS and postnatal ECMO treatment. Although TTF-1 appears to play an important role in lung morphogenesis, a pivotal role in human lung development is not likely.
Hösgör
M
M
Departments of Pediatric Surgery and Pathology, Sophia Children's Hospital, Rotterdam, The Netherlands.
Ijzendoorn
Y
Y
Mooi
W J
WJ
Tibboel
D
D
De Krijger
R R
RR
D005333:Fetus / Q000378:metabolism*; D015870:Gene Expression; D006548:Hernia, Diaphragmatic / Q000196:embryology / Q000378:metabolism; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism*
C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors