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Dasatinib Reduces Lung Inflammation and Fibrosis in Acute Experimental Silicosis.
- Source :
-
PloS one [PLoS One] 2016 Jan 20; Vol. 11 (1), pp. e0147005. Date of Electronic Publication: 2016 Jan 20 (Print Publication: 2016). - Publication Year :
- 2016
-
Abstract
- Silicosis is an occupational lung disease with no effective treatment. We hypothesized that dasatinib, a tyrosine kinase inhibitor, might exhibit therapeutic efficacy in silica-induced pulmonary fibrosis. Silicosis was induced in C57BL/6 mice by a single intratracheal administration of silica particles, whereas the control group received saline. After 14 days, when the disease was already established, animals were randomly assigned to receive DMSO or dasatinib (1 mg/kg) by oral gavage, twice daily, for 14 days. On day 28, lung morphofunction, inflammation, and remodeling were investigated. RAW 264.7 cells (a macrophage cell line) were incubated with silica particles, followed by treatment or not with dasatinib, and evaluated for macrophage polarization. On day 28, dasatinib improved lung mechanics, increased M2 macrophage counts in lung parenchyma and granuloma, and was associated with reduction of fraction area of granuloma, fraction area of collapsed alveoli, protein levels of tumor necrosis factor-α, interleukin-1β, transforming growth factor-β, and reduced neutrophils, M1 macrophages, and collagen fiber content in lung tissue and granuloma in silicotic animals. Additionally, dasatinib reduced expression of iNOS and increased expression of arginase and metalloproteinase-9 in silicotic macrophages. Dasatinib was effective at inducing macrophage polarization toward the M2 phenotype and reducing lung inflammation and fibrosis, thus improving lung mechanics in a murine model of acute silicosis.
- Subjects :
- Acute Disease
Animals
Cell Line
Cytokines metabolism
Disease Models, Animal
Female
Macrophages pathology
Matrix Metalloproteinase 9 metabolism
Mice
Neutrophils pathology
Nitric Oxide Synthase Type II metabolism
Pulmonary Alveoli pathology
Pulmonary Fibrosis metabolism
Pulmonary Fibrosis pathology
Silicosis metabolism
Silicosis pathology
Dasatinib pharmacology
Macrophages metabolism
Neutrophils metabolism
Pulmonary Alveoli metabolism
Pulmonary Fibrosis drug therapy
Silicosis drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 26789403
- Full Text :
- https://doi.org/10.1371/journal.pone.0147005