title: Dasatinib Reduces Lung Inflammation and Fibrosis in Acute Experimental Silicosis.
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.
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Fernanda Ferreira
authors.initials: FF
authors.lastname: Cruz
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Lucas Felipe Bastos
authors.initials: LF
authors.lastname: Horta
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Lígia de Albuquerque
authors.initials: Lde A
authors.lastname: Maia
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Miquéias
authors.initials: M
authors.lastname: Lopes-Pacheco
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: André Benedito
authors.initials: AB
authors.lastname: da Silva
authors.affiliation: Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Marcelo Marco
authors.initials: MM
authors.lastname: Morales
authors.affiliation: Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Cassiano Felippe
authors.initials: CF
authors.lastname: Gonçalves-de-Albuquerque
authors.affiliation: Laboratory of Cellular Pathology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Christina Maeda
authors.initials: CM
authors.lastname: Takiya
authors.affiliation: Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Hugo Caire
authors.initials: HC
authors.lastname: de Castro-Faria-Neto
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Patricia Rieken Macedo
authors.initials: PR
authors.lastname: Rocco
mesh_terms: D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D000069439:Dasatinib / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012829:Silicosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000069439:Dasatinib