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

Oliveira, G. P. and Silva, J. D. and Marques, P. S. and Gonçalves-De-Albuquerque, C. F. and Santos, H. L. and Mócsai, Attila (2015) The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, 36 (4). pp. 1644-1658. ISSN 1015-8987

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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. © 2015 S. Karger AG, Basel.

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