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, A. Mócsai, Hugo C. De Castro-Faria-Neto, Patricia R M Rocco

Research output: Article

15 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 - 2015

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Adult Respiratory Distress Syndrome
Lung
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A
Interleukin-6
Neutrophils
CD95 Antigens
Toll-Like Receptor 4
Transforming Growth Factors
Dimethyl Sulfoxide
Dasatinib
Mechanics
Interleukin-10
Lipopolysaccharides
Pneumonia
Fibrosis
Escherichia coli

ASJC Scopus subject areas

  • Physiology

Cite this

Oliveira, G. P., Silva, J. D., Marques, P. S., Gonçalves-De-Albuquerque, C. F., Santos, H. L., Vascocellos, A. P., ... 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

The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology. / Oliveira, Gisele P.; Silva, Johnatas D.; Marques, Patricia S.; Gonçalves-De-Albuquerque, Cassiano F.; Santos, Heloísa L.; Vascocellos, Ana Paula; Takiya, Christina M.; Morales, Marcelo M.; Pelosi, Paolo; Mócsai, A.; De Castro-Faria-Neto, Hugo C.; Rocco, Patricia R M.

In: Cellular Physiology and Biochemistry, Vol. 36, No. 4, 2015, p. 1644-1658.

Research output: Article

Oliveira, GP, Silva, JD, Marques, PS, Gonçalves-De-Albuquerque, CF, Santos, HL, Vascocellos, AP, Takiya, CM, Morales, MM, Pelosi, P, Mócsai, A, De Castro-Faria-Neto, HC & Rocco, PRM 2015, 'The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology', Cellular Physiology and Biochemistry, vol. 36, no. 4, pp. 1644-1658. https://doi.org/10.1159/000430325
Oliveira GP, Silva JD, Marques PS, Gonçalves-De-Albuquerque CF, Santos HL, Vascocellos AP et al. The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology. Cellular Physiology and Biochemistry. 2015;36(4):1644-1658. https://doi.org/10.1159/000430325
Oliveira, Gisele P. ; Silva, Johnatas D. ; Marques, Patricia S. ; Gonçalves-De-Albuquerque, Cassiano F. ; Santos, Heloísa L. ; Vascocellos, Ana Paula ; Takiya, Christina M. ; Morales, Marcelo M. ; Pelosi, Paolo ; Mócsai, A. ; De Castro-Faria-Neto, Hugo C. ; Rocco, Patricia R M. / The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology. In: Cellular Physiology and Biochemistry. 2015 ; Vol. 36, No. 4. pp. 1644-1658.
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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.",
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T1 - The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology

AU - Oliveira, Gisele P.

AU - Silva, Johnatas D.

AU - Marques, Patricia S.

AU - Gonçalves-De-Albuquerque, Cassiano F.

AU - Santos, Heloísa L.

AU - Vascocellos, Ana Paula

AU - Takiya, Christina M.

AU - Morales, Marcelo M.

AU - Pelosi, Paolo

AU - Mócsai, A.

AU - De Castro-Faria-Neto, Hugo C.

AU - Rocco, Patricia R M

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Acute respiratory distress syndrome

KW - Cytokines

KW - Dasatinib

KW - Histology

KW - Lung mechanics

KW - Toll like receptor-4

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