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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2015-07-01
• Series: Cellular Physiology and Biochemistry
• Subjects: Cytokines; Histology; Lung mechanics; Acute respiratory distress syndrome; Toll like receptor-4; Dasatinib
• Online Access: http://www.karger.com/Article/FullText/430325
• ISSN: 1015-8987; 1421-9778

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.