Published ahead of print on September 21, 2006, doi:10.1165/rcmb.2006-0133OC
© 2007 American Thoracic Society DOI: 10.1165/rcmb.2006-0133OC Epithelial Cell Apoptosis by Fas Ligand–Positive Myofibroblasts in Lung FibrosisLung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, and Department of Pathology, Hadassah–Hebrew University Medical Center, Jerusalem, Israel; and Department of Pathology, Boston University School of Medicine, Boston, Massachusetts Correspondence and requests for reprints should be addressed to Raphael Breuer, M.D., Institute of Pulmonary Medicine, Hadassah–Hebrew University Medical Center, P.O.B. 12,000, Jerusalem, Israel 91120. E-mail: raffi{at}hadassah.org.il
The Fas/Fas ligand (FasL) apoptotic pathway has been shown to be involved in bleomycin-induced lung fibrosis. We examined the hypothesis that myofibroblasts from fibrotic lungs possess a cytotoxic phenotype that causes apoptosis of epithelial cells via the Fas/FasL pathway. We show in vivo epithelial cell apoptosis and associated upregulation of Fas and apoptotic Fas pathway genes in epithelial cells of lungs with bleomycin-induced fibrosis. In addition, we show that FasL surface molecules are overexpressed on
Key Words: apoptosis • epithelial cell • Fas ligand • lung fibrosis • myofibroblast This article has been cited by other articles:
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-SMA–positive cells in mice with bleomycin-induced fibrosis, and in humans with idiopathic pulmonary fibrosis. This enables the molecules to kill Fas-positive epithelial cells. In contrast, FasL-deficient myofibroblasts lose this myofibroblast cytotoxic phenotype, both in vivo and in vitro. In vivo, there was no bleomycin-induced epithelial cell apoptosis, as assessed by specific M30 staining in chimeric FasL-deficient mice that lacked FasL-positive myofibroblasts. In vitro, FasL-positive, but not FasL-negative myofibroblasts, induce mouse lung epithelial cell apoptosis. Thus myofibroblast cytotoxicity may underlie the absence of re-epithelialization, resulting in persistent lung fibrosis. 
