The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology.
Cell Physiol Biochem
; 36(4): 1644-58, 2015.
Article
em En
| MEDLINE
| ID: mdl-26160269
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)-ß 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.
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Base de dados:
MEDLINE
Assunto principal:
Síndrome do Desconforto Respiratório
/
Inibidores de Proteínas Quinases
/
Dasatinibe
/
Pulmão
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article