Fas-ligand-induced apoptosis of respiratory epithelial cells causes disruption of postcanalicular alveolar development.
Premature infants are at risk for bronchopulmonary dysplasia, a complex condition characterized by impaired alveolar development and increased alveolar epithelial apoptosis. The functional involvement of pulmonary apoptosis in bronchopulmonary dysplasia- associated alveolar disruption remains undetermined. The aims of this study were to generate conditional lung-specific Fas-ligand (FasL) transgenic mice and to determine the effects of FasL-induced respiratory epithelial apoptosis on alveolar remodeling in postcanalicular lungs. Transgenic (TetOp)(7)-FasL responder mice, generated by pronuclear microinjection, were bred with Clara cell secretory protein (CCSP)-rtTA activator mice. Doxycycline (Dox) was administered from embryonal day 14 to postnatal day 7, and lungs were studied between embryonal day 19 and postnatal day 21. Dox administration induced marked respiratory epithelium-specific FasL mRNA and protein up-regulation in double-transgenic CCSP-rtTA(+)/(TetOp)(7)-FasL(+) mice compared with single-transgenic CCSP-rtTA(+) littermates. The Dox-induced FasL up-regulation was associated with dramatically increased apoptosis of alveolar type II cells and Clara cells, disrupted alveolar development, decreased vascular density, and increased postnatal lethality. These data demonstrate that FasL-induced alveolar epithelial apoptosis during postcanalicular lung remodeling is sufficient to disrupt alveolar development after birth. The availability of inducible lung-specific FasL transgenic mice will facilitate studies of the role of apoptosis in normal and disrupted alveologenesis and may lead to novel therapeutic approaches for perinatal and adult pulmonary diseases characterized by dysregulated apoptosis.
Women and Infants Hospital, Dept. of Pathology, 101 Dudley St., Providence, RI 02905, USA. mdepaepe@wihri.org
Monique E
ME
De Paepe
Sravanthi
S
Gundavarapu
Umadevi
U
Tantravahi
John R
JR
Pepperell
Sheila A
SA
Haley
Francois I
FI
Luks
Quanfu
Q
Mao
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D015153:Blotting, Western; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology*; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008171:Lung Diseases / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D011650:Pulmonary Alveoli / Q000254:growth & development*; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes
D053222:Fas Ligand Protein