title: The Effects of Dasatinib in Experimental  Acute Respiratory Distress Syndrome  Depend on Dose and Etiology.
abstract: OBJECTIVE
  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.forename: Gisele P
authors.initials: GP
authors.lastname: Oliveira
authors.forename: Johnatas D
authors.initials: JD
authors.lastname: Silva
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Marques
authors.forename: Cassiano F
authors.initials: CF
authors.lastname: Gonçalves-de-Albuquerque
authors.forename: Heloísa L
authors.initials: HL
authors.lastname: Santos
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Vascocellos
authors.forename: Christina M
authors.initials: CM
authors.lastname: Takiya
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Morales
authors.forename: Paolo
authors.initials: P
authors.lastname: Pelosi
authors.forename: Attila
authors.initials: A
authors.lastname: Mócsai
authors.forename: Hugo C
authors.initials: HC
authors.lastname: de Castro-Faria-Neto
authors.forename: Patricia R M
authors.initials: PR
authors.lastname: Rocco
mesh_terms: D000818:Animals; D000069439:Dasatinib / Q000008:administration & dosage / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D000069439:Dasatinib