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Inhibition of Spleen Tyrosine Kinase Attenuates Allergen-Mediated Airway Constriction

2013; American Thoracic Society; Volume: 49; Issue: 6 Linguagem: Inglês

10.1165/rcmb.2013-0200oc

1535-4989

Lily Y. Moy, Yanlin Jia, Michael Caniga, Gissela Lieber, Malgorzata A. Gil, Xiomara Fernandez, Erich E. Sirkowski, Richard E. 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 B. Northrup, Thomas A. Miller, Hani Houshyar, Michael A. Crackower,

Food Allergy and Anaphylaxis Research

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 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.