Increased expression of thyroid transcription factor-1 (TTF-1) in respiratory epithelial cells inhibits alveolarization and causes pulmonary inflammation.
Thyroid transcription factor-1 (TTF-1), a member of the Nkx2 family of homeodomain-containing transcription factors, is expressed in the epithelium of the lung. TTF-1 is a critical regulator of transcription for the surfactant proteins (SP) A, B, and C and is essential for lung morphogenesis. Sites and levels of TTF-1 expression vary during lung morphogenesis and following injury. In order to determine the role of TTF-1 in lung formation, transgenic mice were generated in which TTF-1 was expressed in respiratory epithelial cells of wild-type and Ttf1 null mutant (-/-) mice, using the lung-specific SP-C promoter. The SP-C-Ttf1 transgene did not rescue the severe pulmonary hypoplasia characteristic of the Ttf1 (-/-) mice. Increased expression of TTF-1, however, caused dose-dependent alterations in postnatal lung morphology of wild-type mice. Modest overexpression of TTF-1 caused type II cell hyperplasia and increased the cellular content of SP-B. In contrast, higher expression levels of TTF-1 disrupted alveolar septation, causing emphysema. In mice with the highest transgene expression, TTF-1 caused severe inflammation, pulmonary fibrosis, respiratory failure, and death, associated with eosinophil infiltration and increased expression of eotaxin and IL-6. Increased expression of TTF-1 altered alveolarization and caused chronic pulmonary inflammation, demonstrating that precise regulation of TTF-1 is critical for homeostasis in the postnatal lung.
Wert
Susan E
SE
Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Dey
Chitta R
CR
Blair
Paula A
PA
Kimura
Shioko
S
Whitsett
Jeffrey A
JA
D000818:Animals; D001059:Apoproteins / Q000378:metabolism; D002455:Cell Division; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000254:growth & development*; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000378:metabolism; D051381:Rats; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
D001059:Apoproteins; C000614414:Nkx2-1 protein, mouse; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C046616:pulmonary surfactant apoprotein