Effects of Fas-ligand overexpression on alveolar type II cell growth kinetics in perinatal murine lungs.
We determined the time-specific effects of FasL overexpression on perinatal alveolar type II cell growth kinetics. To achieve temporal overexpression of respiratory epithelium-specific FasL expression, tetracycline inducible CCSP-rtTA/FasL-TetOp transgenic mice were given doxycycline (Dox) from gestational d 14 (E14) to E19 (antenatal treatment group), from postnatal d 1 (P1) to P7 (postnatal group), or from E14 to P7 (combined antenatal and postnatal group). Antenatal Dox administration induced an increase of pulmonary FasL mRNA levels in double transgenic animals up to >300-fold over single transgenic littermate controls, associated with massive fetal respiratory epithelial apoptosis and excessive postnatal lethality. Although animals from the combined antenatal/postnatal Dox treatment group continued to display evidence of increased apoptosis, there was a paradoxical increase in alveolar type II cell proliferation, resulting in a net increase in type II cell density, elevated pulmonary surfactant protein C levels and improved postnatal survival. Postnatal Dox administration was also associated with increased type II cell density, although FasL up-regulation was more variable. In conclusion, these results, and our previous studies, suggest that FasL signaling has dual timing-dependent proapoptotic and proproliferative effects on postcanalicular type II cell kinetics.
de Paepe
Monique E
ME
Department of Pathology, Women and Infants Hospital, and Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02905, USA. mdepaepe@wihri.org
Haley
Sheila A
SA
Lacourse
Zacharie
Z
Mao
Quanfu
Q
D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate
D000900:Anti-Bacterial Agents; D053222:Fas Ligand Protein; D012333:RNA, Messenger; D053148:Caspase 3; D004318:Doxycycline