Epithelial ablation of Bcl-XL increases sensitivity to oxygen without disrupting lung development.
Recent studies indicate that the antiapoptotic Bcl-X(L), one of five isoforms expressed by the Bcl-X gene, protects a variety of cell lines exposed to hyperoxia. However, its role in lung development and protection against oxidative stress in vivo is not known. Here, we show Bcl-X(L) is the predominant isoform expressed in the lung, and the only isoform detected in respiratory epithelium. Because loss of Bcl-X(L) is embryonically lethal, Bcl-X(L) was ablated throughout the respiratory epithelium by mating mice with a floxed exon II of the Bcl-X gene with mice expressing Cre under control of the surfactant protein-C promoter. Interestingly, the loss of Bcl-X(L) in respiratory epithelium was perinatally lethal in approximately 50% of the expected offspring. However, some adult mice lacking the gene were obtained. The epithelial-specific ablation of Bcl-X(L) did not disrupt pulmonary function, the expression of epithelial cell-specific markers, or lung development. However, it shifted the lung toward a proapoptotic state, defined by a reduction in antiapoptotic Mcl-1, an increase in proapoptotic Bak, and increased sensitivity of the respiratory epithelium to hyperoxia. Intriguingly, increased 8-oxoguanine lesions seen during hyperoxia were also evident as lungs transitioned to room air at birth, a time when perinatal lethality in some mice lacking Bcl-X(L) was observed. These findings reveal that the epithelial-specific expression of Bcl-X(L) is not required for proper lung development, but functions to protect respiratory epithelial cells against oxygen-induced toxicity, such as during hyperoxia and the lung's first exposure to ambient air.
Staversky
Rhonda J
RJ
Department of Pediatrics, University of Rochester, NY 14642, USA.
Vitiello
Peter F
PF
Yee
Min
M
Callahan
Linda M
LM
Dean
David A
DA
O'Reilly
Michael A
MA
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D018496:Hyperoxia; D019426:Integrases / Q000378:metabolism; D008168:Lung / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051020:bcl-X Protein / Q000502:physiology*
C494812:Bcl2l1 protein, mouse; D012333:RNA, Messenger; D051020:bcl-X Protein; C024829:8-hydroxyguanine; D006147:Guanine; C045073:Cre recombinase; D019426:Integrases; D010100:Oxygen