β-Catenin in the Alveolar Epithelium Protects from Lung Fibrosis after Intratracheal Bleomycin

Rationale: Alveolar epithelial cells (AECs) play central roles in the response to lung injury and the pathogenesis of pulmonary fibrosis. Objectives: We aimed to determine the role of beta-catenin in alveolar epithelium during bleomycin-induced lung fibrosis. Methods: Genetically modified mice were developed to selectively delete beta-catenin in AECs and were crossed to cell fate reporter mice that express beta-galactosidase (beta gal) in cells of AEC lineage. Mice were given intratracheal bleomycin (0.04 units) and assessed for AEC death, inflammation, lung injury, and fibrotic remodeling. Mouse lung epithelial cells (MLE12) with small interfering RNA knockdown of beta-catenin underwent evaluation for wound closure, proliferation, and bleomycin-induced cytotoxicity. Measurements and Main Results: Increased beta-catenin expression was noted in lung parenchyma after bleomycin. Mice with selective deletion of beta-catenin in AECs had greater AEC death at 1 week after bleomycin, followed by increased numbers of fibroblasts and enhanced lung fibrosis as determined by semiquantitative histological scoring and total collagen content. However, no differences in lung inflammation or protein levels in bronchoalveolar lavage were noted. In vitro, beta-catenin-deficient AECs showed increased bleomycin-induced cytotoxicity as well as reduced proliferation and impaired wound closure. Consistent with these findings, mice with AEC beta-catenin deficiency showed delayed recovery after bleomycin. Conclusions: beta-Catenin in the alveolar epithelium protects against bleomycin-induced fibrosis. Our studies suggest that AEC survival and wound healing are enhanced through beta-catenin-dependent mechanisms. Activation of the developmentally important beta-catenin pathway in AECs appears to contribute to epithelial repair after epithelial injury.