Epithelial Cell Apoptosis by Fas Ligand–Positive Myofibroblasts in Lung Fibrosis
- 1 March 2007
- journal article
- Published by American Thoracic Society in American Journal of Respiratory Cell and Molecular Biology
- Vol. 36 (3), 270-275
- https://doi.org/10.1165/rcmb.2006-0133oc
Abstract
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.Keywords
This publication has 26 references indexed in Scilit:
- Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathwayAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2006
- Early response to bleomycin is characterized by different cytokine and cytokine receptor profiles in lungsAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2004
- Detection of the M30 Neoepitope as a New Tool to Quantify Liver ApoptosisAmerican Journal of Clinical Pathology, 2004
- Possible Role of Apoptosis in the Pathogenesis of Bleomycin-Induced SclerodermaJournal of Investigative Dermatology, 2004
- Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP)Journal of Clinical Pathology, 2001
- Induction of Murine Hepatocyte Death by Membrane-Bound CD95 (Fas/APO-1)-Ligand: Characterization of an In Vitro SystemHepatology, 2000
- Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosisJCI Insight, 1999
- A Fas pathway to pulmonary fibrosisJCI Insight, 1999
- Expression of B7–1, B7–2, and Interleukin–12 in Anti–Fas Antibody–Induced Pulmonary Fibrosis in MiceInternational Archives of Allergy and Immunology, 1999
- Bleomycin-induced pulmonary fibrosis: Correlation of biochemical, physiological, and histological changesToxicology and Applied Pharmacology, 1981