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

¹ Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, ² Division of Nephrology, Department of Medicine, ³ Department of Cell and Developmental Biology, ⁴ Department of Cancer Biology, Vanderbilt University School of Medicine; and ⁵ Department of Veterans Affairs Medical Center, Nashville, Tennessee

Correspondence and requests for reprints should be addressed to William E. Lawson, M.D., Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, TN 37232-2650. E-mail: william.lawson{at}vanderbilt.edu

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 -smooth muscle actin.

Measurements and Main Results: In vitro, primary type II alveolar epithelial cells undergo phenotypic changes of EMT when exposed to transforming growth factor-β₁ and epidermal growth factor with loss of prosurfactant protein C and E-cadherin and gain of S100A4 and type I procollagen. In vivo, using cell fate reporter mice, approximately one-third of S100A4-positive fibroblasts were derived from lung epithelium 2 weeks after bleomycin administration. From bone marrow chimera studies, one-fifth of S100A4-positive fibroblasts were derived from bone marrow at this same time point. Myofibroblasts rarely derived from EMT or bone marrow progenitors.

Conclusions: Both EMT and bone marrow progenitors contribute to S100A4-positive fibroblasts in bleomycin-induced lung fibrosis. However, neither origin is a principal contributor to lung myofibroblasts.

Key Words: epithelial–mesenchymal transition • fibroblasts • S100A4 • lung epithelium

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Fibroblasts are the effector cells in pulmonary fibrosis, responsible for the deposition of collagen and other extracellular matrix. Multiple origins are implicated for the lung fibroblast population, including the possibility that these cells arise through epithelial–mesenchymal transition (EMT). What This Study Adds to the Field Both EMT and bone marrow progenitors contribute to S100A4-positive fibroblasts in bleomycin-induced lung fibrosis. However, neither origin is a principal contributor to lung myofibroblasts.