The Yin and Yang of Tyrosine Kinase Inhibition During Experimental Polymicrobial Sepsis

Frontiers in Immunology
Cassiano Felippe Gonçalves-de-AlbuquerqueHugo Caire de Castro-Faria-Neto

Abstract

Neutrophils are the first cells of our immune system to arrive at the site of inflammation. They release cytokines, e.g., chemokines, to attract further immune cells, but also actively start to phagocytose and kill pathogens. In the case of sepsis, this tightly regulated host defense mechanism can become uncontrolled and hyperactive resulting in severe organ damage. Currently, no effective therapy is available to fight sepsis; therefore, novel treatment targets that could prevent excessive inflammatory responses are warranted. Src Family tyrosine Kinases (SFK), a group of tyrosine kinases, have been shown to play a major role in regulating immune cell recruitment and host defense. Leukocytes with SFK depletion display severe spreading and migration defects along with reduced cytokine production. Thus, we investigated the effects of dasatinib, a tyrosine kinase inhibitor, with a strong inhibitory capacity on SFKs during sterile inflammation and polymicrobial sepsis in mice. We found that dasatinib-treated mice displayed diminished leukocyte adhesion and extravasation in tumor necrosis factor-α-stimulated cremaster muscle venules in vivo. In polymicrobial sepsis, sepsis severity, organ damage, and clinical outcome improved in a d...Continue Reading

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Citations

Mar 24, 2020·Thyroid : Official Journal of the American Thyroid Association·Flavia Fonseca BloiseTânia Maria Ortiga-Carvalho
Dec 13, 2018·Oxidative Medicine and Cellular Longevity·Isabel Matos Medeiros-de-MoraesAdriana Ribeiro Silva
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Jul 1, 2020·International Journal of Molecular Sciences·Adriana R SilvaCassiano F Gonçalves-de-Albuquerque
Jan 21, 2021·International Journal of Molecular Sciences·Márcia V de CarvalhoAdriana R Silva

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Methods Mentioned

BETA
lavage
flow cytometry
FACS
Optical
ELISA

Software Mentioned

Image J
ARRIVE
Fiji
Pro Plus
IBIDI Chemotaxis
Image
Circusoft

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