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Fibroblast proliferation induced by silica-exposed human alveolar macrophages
G P Brown1, M Monick, G W Hunninghake
1Department of Internal Medicine, Veterans Administration Hospital, Iowa City, Iowa.
Abstract:
Inhalation of silica dust is an important cause of pulmonary fibrosis. In these studies, we demonstrate that supernatants of silica-stimulated human alveolar macrophages cause significantly (p less than 0.05) greater amounts of fibroblast proliferation than do supernatants of macrophages stimulated with optimal amounts of endotoxin (LPS). The amount of fibroblast proliferation was similar (p greater than 0.2) in the presence of supernatants of LPS-stimulated macrophages and supernatants of unstimulated adherent macrophages. When macrophages were stimulated with LPS in the presence of indomethacin (to inhibit the cyclooxygenase pathway of arachidonic acid), the supernatants stimulated the same amount of proliferation of fibroblasts as did supernatants of silica-stimulated macrophages. Indomethacin did not increase the growth factor activity of supernatants of silica-stimulated or unstimulated macrophages. Consistent with these observations, supernatants of LPS-stimulated macrophages contained 25.5 +/- 3.8 nM of PGE2, whereas supernatants of silica-stimulated macrophages and unstimulated macrophages contained essentially no PGE2. These findings were confirmed by high performance liquid chromatography. The amounts of PGE2 present in supernatants of LPS-stimulated macrophages were sufficient to cause a 75% reduction in the proliferation of maximally stimulated fibroblasts. These studies suggest that silica may be a very effective stimulus for fibroblast proliferation in vivo since it causes macrophages to release growth factors for fibroblasts without triggering the release of PGE2, an inhibitor of fibroblast proliferation.
Insights
Silica dust inhalation triggers human alveolar macrophages to release fibroblast growth factors, promoting pulmonary fibrosis. Unlike LPS stimulation, silica does not induce PGE2, a fibroblast proliferation inhibitor.
Area of Science:
- Immunology
- Cell Biology
- Pulmonary Medicine
Background:
- Silica dust inhalation is a significant etiological factor in pulmonary fibrosis.
- Alveolar macrophages play a critical role in the pathogenesis of lung diseases.
- Fibroblast proliferation is a key event in the development of fibrotic lung conditions.
Purpose of the Study:
- To investigate the effect of silica-stimulated human alveolar macrophages on fibroblast proliferation.
- To compare the fibroblast proliferation-inducing capacity of silica-stimulated macrophages with lipopolysaccharide (LPS)-stimulated macrophages.
- To elucidate the role of prostaglandin E2 (PGE2) in modulating macrophage-induced fibroblast proliferation.
Main Methods:
- Human alveolar macrophages were stimulated with silica or LPS.
- Supernatants from stimulated macrophages were collected and applied to fibroblasts.
- Fibroblast proliferation was quantified.
- PGE2 levels in macrophage supernatants were measured using high-performance liquid chromatography (HPLC).
- The effect of indomethacin (a cyclooxygenase inhibitor) on macrophage supernatants was assessed.
Main Results:
- Supernatants from silica-stimulated macrophages induced significantly greater fibroblast proliferation compared to LPS-stimulated or unstimulated macrophages.
- LPS-stimulated macrophages released substantial amounts of PGE2 (25.5 +/- 3.8 nM), which inhibited fibroblast proliferation.
- Silica-stimulated and unstimulated macrophages released negligible amounts of PGE2.
- Indomethacin treatment of LPS-stimulated macrophages resulted in supernatants that induced fibroblast proliferation comparable to silica-stimulated macrophages.
- Indomethacin did not enhance the growth factor activity of silica-stimulated or unstimulated macrophage supernatants.
Conclusions:
- Silica exposure stimulates alveolar macrophages to release potent fibroblast growth factors.
- Macrophages stimulated by silica promote fibroblast proliferation without releasing inhibitory PGE2.
- These findings suggest silica is a potent in vivo stimulus for fibroblast proliferation, contributing to pulmonary fibrosis development.