Role for the TGF-beta/BMP and beta-catenin signaling pathways in lung development and repair

The conducting airway epithelium is lined with a heterogeneous population of secretory and ciliated cells. Inflammation and inhaled toxicants can damage the epithelial lining, which is rapidly repaired through a tissue stem cell-mediated process. Incomplete and disrupted repair contribute to the development of chronic lung disease. The signaling pathways that orchestrate airway epithelial repair are largely unknown, however roles for both Wnt/beta-catenin and TGFbeta/BMP signaling have been suggested. The TGFbeta/BMP family of signaling molecules regulates lung branching morphogensis, epithelial repair and carcinogenesis. To determine the role of Smad4 in these processes, cell type specific deletion of Smad4 was used to block Smad-dependent signaling. Loss of Smad4-dependent signaling during embryogenesis markedly increased airway branching. These mice later developed adenomas, reflecting the role of Smad4 in lung tumor suppression. Epithelial repair was not influenced by loss of Smad-dependent signaling. These data indicated a role for Smad-dependent signaling in branching morphogenesis and tumor suppression, but not epithelial repair.;Next, the necessity for Wnt/beta-catenin signaling in airway epithelial homeostasis and repair was determined. Wnt/beta-catenin signaling regulates epithelial homeostasis in the intestine and skin, but the role of this pathway in the airways is unknown. This hypothesis was tested through the generation of mice with airway-specific loss of beta-catenin. A beta-catenin null airway epithelium repaired normally in an in vivo injury model system. No defects in epithelial homeostasis or differentiation were seen in the absence of beta-catenin. We concluded that beta-catenin is not a principal regulator of airway homeostasis in the adult conducting airway epithelium. Finally, my dissertation research further characterized the molecular phenotype of the airway secretory cell population. Two ablation models were used to deplete secretory cells in vivo. Microarray analysis was performed following secretory cell ablation to identify genes that might be expressed within the secretory population. Four novel secretory cell markers were identified by this approach. In conclusion, this dissertation reports on the determination of roles for Wnt/beta-catenin and TGFbeta/BMP signaling in the airway epithelium and describes further characterization of the molecular repertoire of the airway secretory cell population.