Epithelial Ablation of Bcl-XL Increases Sensitivity to Oxygen without Disrupting Lung Development
Year: 2009
Type: article
Abstract: 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.
Institutions: University of Rochester Medicine, University of Rochester
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Electroporation-mediated Pulmonary Gene Transfer for Acute Lung Injury, G208308110, G2189277278, G2289186176, Cytoplasmic trafficking of non-viral gene therapy vectors, Cell survival and death in oxidant lung injury, G3405300570, G3806731320, G4669862682, Alveolar Epithelial Cell-Specific Gene Therapy Plasmids, Vascular smooth muscle specific gene therapy vectors, Effect of Neonatal Hyperoxia on Alveolar Development and Infection, G682100620, G8185607770, G9000020184, Environmental Agents as Modulators of Disease Processes
OpenAlex ID: W2170348681