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Transforming growth factor-beta is generated in the course of hypersensitivity pneumonitis: contribution to collagen
1Unité de Recherche Pulmonaire, Centre Hospitalier Universitaire de Sherbrooke, Quebec, Canada.
Abstract:
Mice of the C57BL/6 strain were instilled with optimal doses (150 micrograms/day for 3 days/wk) of the thermophilic actinomycete Faeni rectivirgula (also known as Saccharopolyspora rectivirgula or Micropolyspora faeni) to induce a hypersensitivity pneumonitis inflammation that mimics the human disease affecting certain occupational groups. This mouse model was characterized by a very significant alveolitis (3-fold increase in bronchoalveolar lavage [BAL] cell number at 48 h and a 10-fold increase at 3 wk). Also, total lung transforming growth factor (TGF-beta) was shown to be elevated in treated mice as early as 1 wk after the first instillation and increased gradually to 2.5 micrograms/lung at 3 wk (approximately 0.3 microgram/lung in saline-instilled controls). Intranasal instillation with F. rectivirgula was also associated with very significant increases in lung fibroblast collagen synthesis, starting at 2 wk. BAL macrophages from mice instilled with F. rectivirgula were found to release significantly more TGF-beta upon in vitro stimulation with zymosan beads than did BAL macrophages from saline-instilled mice. Finally, we show that supernatants from activated BAL macrophages of mice given F. rectivirgula increased quite significantly collagen synthesis in normal mouse lung fibroblasts. This increase could be abrogated by treating conditioned medium with a rabbit antibody against TGF-beta. Collectively, these data suggest that TGF-beta is generated in the course of experimental mouse hypersensitivity pneumonitis and contributes significantly to collagen synthesis.
Insights
This study shows that exposure to Faeni rectivirgula in mice causes hypersensitivity pneumonitis and increases lung collagen. Transforming growth factor-beta (TGF-beta) plays a key role in this fibrotic response.
Area of Science:
- Immunology
- Pulmonary Medicine
- Toxicology
Background:
- Hypersensitivity pneumonitis (HP) is an immune-mediated lung disease caused by occupational exposures.
- A mouse model is needed to study HP pathogenesis and potential treatments.
Purpose of the Study:
- To establish and characterize a mouse model of HP induced by Faeni rectivirgula.
- To investigate the role of transforming growth factor-beta (TGF-beta) in HP-associated lung fibrosis.
Main Methods:
- Mice were instilled with Faeni rectivirgula to induce HP.
- Bronchoalveolar lavage (BAL) cell counts, lung TGF-beta levels, and lung fibroblast collagen synthesis were measured.
- TGF-beta production by BAL macrophages and its effect on fibroblast collagen synthesis were assessed.
Main Results:
- Faeni rectivirgula instillation induced significant alveolitis and elevated lung TGF-beta levels.
- Increased lung fibroblast collagen synthesis was observed, correlating with TGF-beta levels.
- Activated BAL macrophages produced more TGF-beta, which enhanced collagen synthesis in fibroblasts.
Conclusions:
- Faeni rectivirgula exposure effectively models HP in mice.
- TGF-beta is a key mediator in the development of lung fibrosis in this HP model.