Background
Spleen Tyrosine Kinase (SYK) is a key activator of signaling pathways downstream of multiple surface receptors implicated in asthma. SYK function has been extensively studied in Last cells downstream of the high-affinity IgE receptor (FcεR1). Most studies evaluating SYK function in preclinical models have relied on poorly selective compounds, anti-sense oligonucleotides, or SYK knockout mice. Here we describe the characterization of SYK mechanism in multiple in vivo model settings.
Materials and methods
The effect of SYK inhibitor MRK-A on allergic airway responses was evaluated in IgE-mediated tracheal extravasation in rat, Brown Norway Ova rat models of allergic inflammation and the sheep inhaled ascaris allergen challenge model.
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Results
MRK-A dose-dependently blocked IgE-mediated tracheal extravasation in rat. In a Brown Norway rat ovalbumin-sensitized airway challenge model oral dosing of MRK-A led to a dose-dependent inhibition of airway inflammation. Intravenous dosing of MRK-A was able to significantly inhibit both early and late allergen- induced changes in airway resistance in an ascaris-sensitive sheep allergen challenge model as well as airway hyper responsiveness.
Conclusions
Here we demonstrated that SYK mechanism plays a significant role in several in vivo allergen challenge models. This ranges from simple PK/PD mast cells driven models such as the IgE-mediated tracheal extravasation to the more complex and clinically relevant sheep inhaled allergen challenge model.
Open Access
This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License (
https://creativecommons.org/licenses/by/2.0
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.