Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis

H Tanjore, XC Xu, VV Polosukhin… - American journal of …, 2009 - atsjournals.org
H Tanjore, XC Xu, VV Polosukhin, AL Degryse, B Li, W Han, TP Sherrill, D Plieth…
American journal of respiratory and critical care medicine, 2009atsjournals.org
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 …
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: 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.
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