BACKGROUND/AIMS: Evidence suggests that tyrosine-kinase inhibitors may attenuate lung inflammation and fibrosis in experimental acute respiratory distress syndrome (ARDS). We hypothesized that dasatinib, a tyrosine-kinase inhibitor, might act differently depending on the ARDS etiology and the dose. METHODS: C57/BL6 mice were divided to be pre-treated with dasatinib (1mg/kg or 10mg/kg) or vehicle (1% dimethyl-sulfoxide) by oral gavage. Thirty-minutes after pre-treatment, mice were subdivided into control (C) or ARDS groups. ARDS animals received Escherichia coli lipopolysaccharide intratracheally (ARDSp) or intraperitoneally (ARDSexp). A new dose of dasatinib or vehicle was administered at 6 and 24h. RESULTS: Forty-eight hours after ARDS induction, dasatinib 1mg/kg yielded: improved lung morphofunction and reduced cells expressing toll-like receptor (TLR)-4 in lung, independent of ARDS etiology; reduced neutrophil and levels of interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-β in ARDSp. The higher dose of dasatinib caused no changes in lung mechanics, diffuse alveolar damage, neutrophil, or cells expressing TLR4, but increased IL-6, vascular endothelial growth factor (VEGF), and cells expressing Fas receptor in lung in ARDSp. In ARDSexp, it improved lung morphofunction, increased VEGF, and reduced cells expressing TLR4. Conclusion: Dasatinib may have therapeutic potential in ARDS independent of etiology, but careful dose monitoring is required.
BACKGROUND/AIMS: Evidence suggests that tyrosine-kinase inhibitors may attenuate lung inflammation and fibrosis in experimental acute respiratory distress syndrome (ARDS). We hypothesized that dasatinib, a tyrosine-kinase inhibitor, might act differently depending on the ARDS etiology and the dose. METHODS: C57/BL6 mice were divided to be pre-treated with dasatinib (1mg/kg or 10mg/kg) or vehicle (1% dimethyl-sulfoxide) by oral gavage. Thirty-minutes after pre-treatment, mice were subdivided into control (C) or ARDS groups. ARDS animals received Escherichia coli lipopolysaccharide intratracheally (ARDSp) or intraperitoneally (ARDSexp). A new dose of dasatinib or vehicle was administered at 6 and 24h. RESULTS: Forty-eight hours after ARDS induction, dasatinib 1mg/kg yielded: improved lung morphofunction and reduced cells expressing toll-like receptor (TLR)-4 in lung, independent of ARDS etiology; reduced neutrophil and levels of interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-β in ARDSp. The higher dose of dasatinib caused no changes in lung mechanics, diffuse alveolar damage, neutrophil, or cells expressing TLR4, but increased IL-6, vascular endothelial growth factor (VEGF), and cells expressing Fas receptor in lung in ARDSp. In ARDSexp, it improved lung morphofunction, increased VEGF, and reduced cells expressing TLR4. Conclusion:Dasatinib may have therapeutic potential in ARDS independent of etiology, but careful dose monitoring is required.
Authors: Priscila J Carneiro; Amanda L Clevelario; Gisele A Padilha; Johnatas D Silva; Jamil Z Kitoko; Priscilla C Olsen; Vera L Capelozzi; Patricia R M Rocco; Fernanda F Cruz Journal: Front Physiol Date: 2017-03-15 Impact factor: 4.566
Authors: Johann Bartko; Leopold Stiebellehner; Ulla Derhaschnig; Christian Schoergenhofer; Michael Schwameis; Helmut Prosch; Bernd Jilma Journal: Br J Clin Pharmacol Date: 2016-01-15 Impact factor: 4.335
Authors: Cassiano Felippe Gonçalves-de-Albuquerque; Ina Rohwedder; Adriana Ribeiro Silva; Alessandra Silveira Ferreira; Angela R M Kurz; Céline Cougoule; Sarah Klapproth; Tanja Eggersmann; Johnatas D Silva; Gisele Pena de Oliveira; Vera Luiza Capelozzi; Gabriel Gutfilen Schlesinger; Edlaine Rijo Costa; Rita de Cassia Elias Estrela Marins; Attila Mócsai; Isabelle Maridonneau-Parini; Barbara Walzog; Patricia Rieken Macedo Rocco; Markus Sperandio; Hugo Caire de Castro-Faria-Neto Journal: Front Immunol Date: 2018-04-30 Impact factor: 7.561