1. Dasatinib Reduces Lung Inflammation and Fibrosis in Acute Experimental Silicosis.
- Author
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Cruz FF, Horta LF, Maia Lde A, Lopes-Pacheco M, da Silva AB, Morales MM, Gonçalves-de-Albuquerque CF, Takiya CM, de Castro-Faria-Neto HC, and Rocco PR
- 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
- 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.
- Published
- 2016
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