The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology

Gisele P. Oliveira, Johnatas D. Silva, Patricia S. Marques, Cassiano F. Gonçalves-De-Albuquerque, Heloísa L. Santos, Ana Paula Vascocellos, Christina M. Takiya, Marcelo M. Morales, Paolo Pelosi, Attila Mócsai, Hugo C. De Castro-Faria-Neto, Patricia R.M. Rocco

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16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1644-1658
Number of pages15
JournalCellular Physiology and Biochemistry
Volume36
Issue number4
DOIs
Publication statusPublished - Jan 1 2015

Keywords

  • Acute respiratory distress syndrome
  • Cytokines
  • Dasatinib
  • Histology
  • Lung mechanics
  • Toll like receptor-4

ASJC Scopus subject areas

  • Physiology

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  • Cite this

    Oliveira, G. P., Silva, J. D., Marques, P. S., Gonçalves-De-Albuquerque, C. F., Santos, H. L., Vascocellos, A. P., Takiya, C. M., Morales, M. M., Pelosi, P., Mócsai, A., De Castro-Faria-Neto, H. C., & Rocco, P. R. M. (2015). The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology. Cellular Physiology and Biochemistry, 36(4), 1644-1658. https://doi.org/10.1159/000430325