Epithelial cell apoptosis by fas ligand-positive myofibroblasts in lung fibrosis.
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 alpha-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.
Golan-Gerstl
Regina
R
Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, and Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Wallach-Dayan
Shulamit B
SB
Amir
Gail
G
Breuer
Raphael
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000494:pharmacology; D002678:Chimera; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D053222:Fas Ligand Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000473:pathology*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D019014:fas Receptor; D001761:Bleomycin