Contribution of Epithelial-derived Fibroblasts to Bleomycin-induced Lung Fibrosis

Abstract

Rationale: Lung fibroblasts are key mediators of fibrosis resulting in accumulation of excessive interstitial collagen and extracellular matrix, but their origins are not well defined.Objectives: We aimed to elucidate the contribution of lung epithelium–derived fibroblasts via epithelial–mesenchymal transition (EMT) in the intratracheal bleomycin model.Methods: Primary type II alveolar epithelial cells were cultured from Immortomice and exposed to transforming growth factor-β1 and epidermal growth factor. Cell fate reporter mice that permanently mark cells of lung epithelial lineage with β-galactosidase were developed to study EMT, and bone marrow chimeras expressing green fluorescent protein under the control of the fibroblast-associated S100A4 promoter were generated to examine bone marrow–derived fibroblasts. Mice were given intratracheal bleomycin (0.08 unit). Immunostaining was performed for S100A4, β-galactosidase, green fluorescent protein, and α-smooth muscle actin.Measurements and Main Results: I...