Inhibition of Spleen tyrosine kinase attenuates allergen-mediated airway constriction

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. AbrahamAlan Northrup, Thomas Miller, Hani Houshyar, Michael A. Crackower

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1085-1092
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue number6
DOIs
StatePublished - Dec 2013
Externally publishedYes

Keywords

  • Allergy
  • Asthma
  • Inflammation
  • Spleen tyrosine kinase

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

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