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Silica-induced pulmonary fibrosis involves the reaction of particles with interstitial rather than alveolar
D H Bowden1, C Hedgecock, I Y Adamson
1Department of Pathology, University of Manitoba, Winnipeg, Canada.
Abstract:
Macrophage-derived products have been implicated in fibroblast stimulation following particle deposition in the lung. To assess the role of macrophages in the alveolus versus those in the interstitium in the induction of pulmonary fibrosis, we compared the pulmonary response to silica when phagocytosis occurred predominantly in each of these compartments. One group of mice received intratracheal silica which was phagocytosed largely by alveolar macrophages (AM). A second group was exposed to whole body irradiation prior to receiving the same dose of silica. This prevented the usual efflux of PMN and monocytes into the air sacs, allowing passage of silica particles across the alveolar epithelium to reach the interstitial macrophages (IM). In the irradiation plus silica group, many large interstitial granulomas were formed at 2-4 weeks, and collagen levels were significantly greater than in all other groups at 16 weeks. More silica was found in a lung tissue residue and in lymph nodes of these animals. Pulmonary fibrosis was limited to interstitial areas where there was a high level of retained silica, whereas peripheral regions of the lung, where free AM containing silica were found, did not show fibrosis of the alveolar walls. The results suggest that factors secreted by IM in response to silica are more effective in stimulating fibrogenesis than secretions made by the AM into the alveolar space.
Insights
Interstitial macrophages, not alveolar macrophages, drive silica-induced pulmonary fibrosis. This suggests targeting interstitial macrophages may be key for treating lung fibrosis.
Area of Science:
- Pulmonary Medicine
- Immunology
- Toxicology
Background:
- Macrophage-derived products are implicated in fibroblast stimulation and lung fibrosis after particle exposure.
- The distinct roles of alveolar macrophages (AM) and interstitial macrophages (IM) in initiating pulmonary fibrosis remain unclear.
Purpose of the Study:
- To compare the roles of AM and IM in the induction of pulmonary fibrosis following silica deposition in the lung.
- To determine whether silica phagocytosis by AM or IM leads to greater fibrotic responses.
Main Methods:
- Mice received intratracheal silica, with phagocytosis predominantly by AM.
- A separate group underwent whole-body irradiation before silica exposure to direct particle deposition towards IM.
- Pulmonary fibrosis was assessed by histological analysis and collagen levels at 16 weeks.
Main Results:
- Silica exposure leading to IM phagocytosis resulted in significant interstitial granuloma formation and increased collagen levels compared to AM phagocytosis.
- Fibrosis was localized to interstitial areas with high silica retention, while alveolar walls with AM-containing silica showed no fibrosis.
- Increased silica was found in lung tissue residue and lymph nodes in the IM-dominant group.
Conclusions:
- Interstitial macrophages (IM), upon silica phagocytosis, are more potent inducers of pulmonary fibrosis than alveolar macrophages (AM).
- Factors secreted by IM are more effective in stimulating fibrogenesis compared to those secreted by AM.
- Targeting IM may offer a therapeutic strategy for silica-induced lung fibrosis.