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Fas ligand triggers pulmonary silicosis
V M Borges1, H Falcão, J H Leite-Júnior
1Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21944-970, Rio de Janeiro, Brazil.
Abstract:
We investigated the role of Fas ligand in murine silicosis. Wild-type mice instilled with silica developed severe pulmonary inflammation, with local production of tumor necrosis factor (TNF)-alpha, and interstitial neutrophil and macrophage infiltration in the lungs. Strikingly, Fas ligand-deficient generalized lymphoproliferative disease mutant (gld) mice did not develop silicosis. The gld mice had markedly reduced neutrophil extravasation into bronchoalveolar space, and did not show increased TNF-alpha production, nor pulmonary inflammation. Bone marrow chimeras and local adoptive transfer demonstrated that wild-type, but not Fas ligand-deficient lung macrophages recruit neutrophils and initiate silicosis. Silica induced Fas ligand expression in lung macrophages in vitro and in vivo, and promoted Fas ligand-dependent macrophage apoptosis. Administration of neutralizing anti-Fas ligand antibody in vivo blocked induction of silicosis. Thus, Fas ligand plays a central role in induction of pulmonary silicosis.
Insights
Fas ligand is crucial for developing silicosis, a lung disease caused by silica dust. Blocking Fas ligand prevents silica-induced lung inflammation and neutrophil infiltration in mice.
Area of Science:
- Immunology
- Pulmonary Medicine
- Toxicology
Background:
- Silicosis is a severe lung disease characterized by inflammation and fibrosis.
- The precise mechanisms initiating silicosis, particularly the role of immune mediators, require further elucidation.
Purpose of the Study:
- To investigate the role of Fas ligand in the pathogenesis of silica-induced lung injury.
- To determine if Fas ligand is essential for the development of murine silicosis.
Main Methods:
- Comparison of wild-type and Fas ligand-deficient (gld) mice following silica instillation.
- Assessment of pulmonary inflammation, neutrophil infiltration, and cytokine production (TNF-alpha).
- Bone marrow chimeras and adoptive transfer experiments to identify the cell source of Fas ligand.
- In vitro and in vivo studies on silica-induced Fas ligand expression and macrophage apoptosis.
- Administration of anti-Fas ligand antibodies to assess therapeutic potential.
Main Results:
- Wild-type mice developed severe silicosis with pulmonary inflammation and neutrophil infiltration.
- Fas ligand-deficient mice showed significantly reduced inflammation, neutrophil extravasation, and TNF-alpha production.
- Lung macrophages from wild-type mice, but not Fas ligand-deficient ones, were responsible for neutrophil recruitment and silicosis initiation.
- Silica exposure upregulated Fas ligand expression in lung macrophages, leading to Fas ligand-dependent apoptosis.
- Blocking Fas ligand with antibodies prevented the induction of silicosis.
Conclusions:
- Fas ligand is a critical mediator in the induction of pulmonary silicosis.
- Targeting Fas ligand may represent a therapeutic strategy for preventing or treating silicosis.