Inhibition of Spleen tyrosine kinase attenuates allergen-mediated airway constriction

Spleen tyrosine kinase (SYK) is a key activator of signaling pathways downstreamofmultiple surfacereceptorsimplicatedinasthma. 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 haveusedapotentand selectivepharmacological 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 evaluatedin arat passive anaphylaxis model and ratand sheep inhaled allergenchallenge models,aswellasanexvivo modelofallergen- mediatedairwayconstrictioninratsandcynomolgus 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 showeda complete attenuation with treatmentof a SYK inhibitor, aswellas a complete block of allergen-induced serotonin release. Similarly, allergen-mediated airwayconstrictionwasattenuatedinexvivostudiesfromnonhuman 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.