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Published ahead of print on June 25, 2009, doi:10.1164/rccm.200903-0322OC

Am. J. Respir. Crit. Care Med., Volume 180, Number 7, October 2009, 657-665

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Submitted on March 2, 2009
Accepted on June 24, 2009

Contribution of Epithelial Derived Fibroblasts to Bleomycin Induced Lung Fibrosis

Harikrishna Tanjore1, Xiaochuan C Xu1, Vasiliy V Polosukhin1, Amber L Degryse1, Bo Li1, Wei Han1, Taylor P Sherrill1, David Plieth2, Eric G Neilson2, Timothy S Blackwell3, and William E Lawson4*

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

* To whom correspondence should be addressed. 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 (AECs) were cultured from Immortomice and exposed to Transforming Growth Factor {beta}1 (TGF{beta}1) and Epidermal Growth Factor (EGF). Cell fate reporter mice that permanently mark cells of lung epithelial lineage with {beta}-galactosidase ({beta}gal) 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, {beta}gal, 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 TGF{beta}1 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.


Key words: EMT • epithelial mesenchymal transition • fibroblasts • S100A4 • lung epithelium






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