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Updated: May 6, 2026
Establishing a Silicosis Rat Model via Exposure of Whole-Body to Respirable Silica
Published on: October 28, 2022
Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in
Hanyujie Kang1, Xueqing Gu1, Siyu Cao1
1Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
Background:
Silicosis is a lethal occupational disease caused by long-term exposure to respirable silica dust. Pulmonary macrophages play a crucial role in mediating the initiation of silicosis. However, the phenotypic and functional heterogeneities of pulmonary macrophages in silicosis have not been well-studied.
Methods:
The silicosis mouse model was established by intratracheal administration of silica suspension. Bronchoalveolar lavage fluids (BALFs) of mice were collected for the multiplex cytokine analysis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed to reveal the heterogeneity and spatial localization of macrophages in the lung tissues. The formation of the fibrotic nodules was characterized by histology, hydroxyproline assay, and immunohistochemical staining, respectively. The expression of the pro-inflammatory or pro-fibrotic genes was investigated by quantitative polymerase chain reaction (qPCR).
Results:
We found that the level of pro-inflammatory cytokines and chemokines is significantly increased in the BALFs of silicosis mice. Apparent collagen deposition can also be observed in the silicotic lung tissues. By scRNA-seq, we have identified a subpopulation of Mmp12hi macrophages significantly expanding in the lung tissues of mice with silicosis. Spatial transcriptomics analysis further confirmed that the Mmp12hi macrophages are mainly enriched in silicosis nodules. Pseudotime trajectory showed that these Mmp12hi macrophages, highly expressing both pro-inflammatory and pro-fibrotic genes, are derived from Ly6c+ monocytes. Additionally, 4-octyl itaconate (4-OI) treatment, which can alleviate pulmonary fibrosis in silicosis mice, also reduces the enrichment of the Mmp12hi macrophages. Moreover, we found a subset of macrophages in BALFs derived from patients with silicosis exhibited similar characteristics of Mmp12hi macrophages in silicosis mice models.
Conclusions:
Our study suggested that a group of Mmp12hi macrophages highly express both pro-inflammatory and pro-fibrotic factors in silicosis mice, and thus may contribute to the progression of fibrosis. The findings have proposed new insights for understanding the heterogeneity of lung macrophages in silicosis, suggesting that the subset of Mmp12hi macrophages may be a potential therapy target to further halt the progression of silicosis.
Insights
This study identifies Mmp12-high macrophages as key drivers of silicosis progression by promoting inflammation and fibrosis. Targeting these specific macrophages offers a potential therapeutic strategy for this debilitating lung disease.
Area of Science:
- Pulmonary immunology
- Occupational lung diseases
- Fibrosis research
Background:
- Silicosis is a severe occupational lung disease caused by silica dust inhalation.
- Pulmonary macrophages are critical in silicosis initiation, but their heterogeneity is poorly understood.
Purpose of the Study:
- To investigate the phenotypic and functional heterogeneity of pulmonary macrophages in silicosis.
- To identify specific macrophage subsets involved in silicosis pathogenesis.
- To explore potential therapeutic targets for silicosis.
Main Methods:
- Established a silicosis mouse model via silica suspension instillation.
- Analyzed bronchoalveolar lavage fluids (BALFs) for cytokine levels.
- Utilized single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to characterize lung macrophages.
- Assessed lung fibrosis through histology, hydroxyproline assay, and immunohistochemistry.
- Quantified gene expression of inflammatory and fibrotic markers using qPCR.
Main Results:
- Silicotic mice exhibited elevated pro-inflammatory cytokines and chemokines in BALFs and significant collagen deposition.
- scRNA-seq identified an expansion of Mmp12-high macrophages in silicotic lungs.
- Spatial transcriptomics localized Mmp12-high macrophages within fibrotic nodules.
- These macrophages, derived from Ly6c+ monocytes, express high levels of pro-inflammatory and pro-fibrotic genes.
- Treatment with 4-octyl itaconate (4-OI) reduced Mmp12-high macrophage enrichment and alleviated pulmonary fibrosis.
- Macrophages from human silicosis patients showed similar Mmp12-high characteristics.
Conclusions:
- Mmp12-high macrophages are a distinct subset in silicosis, expressing pro-inflammatory and pro-fibrotic factors that drive disease progression.
- These findings illuminate lung macrophage heterogeneity in silicosis.
- Mmp12-high macrophages represent a promising therapeutic target for halting silicosis progression.
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