Tanjore H, Xu XC, Polosukhin VV, Degryse AL, Li B, Han W, Sherrill TP, Plieth D, Neilson EG, Blackwell TS, Lawson WE
Contribution of Epithelial Derived Fibroblasts to Bleomycin Induced Lung Fibrosis. [JOURNAL ARTICLE]
Am J Respir Crit Care Med 2009 Jun 25.
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 (AECs) were cultured from Immortomice and exposed to Transforming Growth Factor beta1 (TGFbeta1) and Epidermal Growth Factor (EGF). Cell fate reporter mice that permanently mark cells of lung epithelial lineage with beta-galactosidase (betagal) were developed to study EMT, while bone marrow chimeras expressing green fluorescent protein (GFP) under control of the fibroblast associated S100A4 promoter were generated to examine bone marrow derived fibroblasts. Mice were given intratracheal bleomycin (0.08 units). Immunostaining was performed for S100A4, betagal, GFP, and alpha-smooth muscle actin (alpha-SMA).
MEASUREMENTS AND MAIN RESULTS: In vitro, primary type II AECs undergo phenotypic changes of EMT when exposed to TGFbeta1 and EGF with loss of pro-surfactant protein C and e-cadherin and gain of S100A4 and type I pro-collagen. In vivo, using cell fate reporter mice, approximately 1/3 of S100A4+ fibroblasts were derived from lung epithelium at 2 weeks post bleomycin. From bone marrow chimera studies, 1/5 of S100A4+ 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+ fibroblasts in bleomycin induced lung fibrosis. However, neither origin is a principal contributor to lung myofibroblasts.
More from this journal |
