• Lily Y Moy, Yanlin Jia, Michael Caniga, Gissela Lieber, Malgorzata Gil, Xiomara Fernandez, Erich Sirkowski, Richard Miller, Jessica P Alexander, Hyun-Hee Lee, John D Shin, J Michael Ellis, Hongmin Chen, Alan Wilhelm, Hongshi Yu, Stella Vincent, Richard W Chapman, Nancy Kelly, Emily Hickey, William M Abraham, Alan Northrup, Thomas Miller, Hani Houshyar, and Michael A Crackower.
• 1 In Vivo Pharmacology.
• Am. J. Respir. Cell Mol. Biol. 2013 Dec 1; 49 (6): 1085-92.

AbstractSpleen 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 mast cells downstream of the high-affinity IgE receptor, FcεR1. Preclinical studies have demonstrated a role for SYK in models of allergic inflammation, but a role in airway constriction has not been demonstrated. Here, we have used a potent and selective pharmacological inhibitor of SYK to determine the role of SYK in allergen-mediated inflammation and airway constriction in preclinical models. Attenuation of allergic airway responses was evaluated in a rat passive anaphylaxis model and rat and sheep inhaled allergen challenge models, as well as an ex vivo model of allergen-mediated airway constriction in rats and cynomolgus monkeys. Pharmacological inhibition of SYK dose-dependently blocked IgE-mediated tracheal plasma extravasation in rats. In a rat ovalbumin-sensitized airway challenge model, oral dosing with an SYK inhibitor led to a dose-dependent reduction in lung inflammatory cells. Ex vivo analysis of allergen-induced airway constriction in ovalbumin-sensitized brown Norway rats showed a complete attenuation with treatment of a SYK inhibitor, as well as a complete block of allergen-induced serotonin release. Similarly, allergen-mediated airway constriction was attenuated in ex vivo studies from nonhuman primate lungs. Intravenous administration of an SYK inhibitor attenuated both early- and late-phase allergen-induced increases in airway resistance in an Ascaris-sensitive sheep allergen challenge model. These data support a key role for SYK signaling in mediating allergic airway responses.

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