Expression of thyroid transcription factor-1 in congenital cystic adenomatoid malformation of the lung.
Congenital cystic adenomatoid malformation (CCAM) is an abnormality of branching morphogenesis of the lung. CCAM types 1, 2, and 3 exhibit a cellular composition that is different from that of CCAM type 4 when evaluated with bronchiolar and alveolar cell markers. Thyroid transcription factor 1 (TTF-1) regulates early lung development. To evaluate the potential role of TTF-1 in the development of CCAM, TTF-1 expression in CCAM was compared to that of fetal lungs at varying gestational ages. Twenty-three CCAM cases (17 type 1, two type 2, two type 3, and two type 4) and 11 fetal lungs (3 pseudoglandular, 4 canalicular, and 4 terminal sac stages) were analyzed using a rabbit polyclonal antiserum to rat TTF-1. Nuclear staining for TTF-1 was observed in ciliated and nonciliated cells of the bronchial and bronchiolar epithelia and in cells lining the distal air spaces by 12 weeks gestational age. By mid-gestation, proximal bronchial cells were TTF-1 negative, except for the basal cells, while TTF-1 staining was maintained in distal bronchiolar and alveolar cells. TTF-1 expression decreased in both bronchial, bronchiolar, and alveolar epithelia with advancing gestational age and cytodifferentiation. At term, TTF-1 expression persisted in a few bronchial and bronchiolar basal cells and in all alveolar type II cells, whereas type I cells were negative. In CCAM, TTF-1 was detected in the nuclei of epithelial cells lining the cysts. TTF-1 was expressed in a majority of the bronchiolar-like epithelial cells of the cysts in CCAM types 1, 2, and 3, where almost 100% of the cells were TTF-1 positive. In contrast, TTF-1 expression in the alveolar-like epithelium of CCAM type 4 cysts was restricted to type II cells and only 30%-60% of the lining cells were TTF-1 positive. These results support the hypothesis that CCAM types 1, 2, and 3 reflect abnormalities in lung morphogenesis and differentiation that are distinct from those for CCAM type 4. The role played by TTF-1 in the development of CCAM, if any, is not clear.
Morotti
R A
RA
Department of Pathology, Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
Gutierrez
M C
MC
Askin
F
F
Profitt
S A
SA
Wert
S E
SE
Whitsett
J A
JA
Greco
M A
MA
D000818:Animals; D001980:Bronchi / Q000002:abnormalities / Q000378:metabolism; D015615:Cystic Adenomatoid Malformation of Lung, Congenital / Q000145:classification / Q000378:metabolism*; D005315:Fetal Diseases / Q000378:metabolism* / Q000473:pathology; D005333:Fetus / Q000002:abnormalities / Q000378:metabolism*; D005865:Gestational Age; D006801:Humans; D007124:Immunoenzyme Techniques; D009687:Nuclear Proteins / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000002:abnormalities / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013961:Thyroid Gland / Q000378:metabolism*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism*
C000614412:NKX2-1 protein, human; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors