Inhibition of spleen tyrosine kinase attenuates allergen-mediated airway constriction

Am J Respir Cell Mol Biol. 2013 Dec;49(6):1085-92. doi: 10.1165/rcmb.2013-0200OC.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / administration & dosage*
  • Animals
  • Ascaris suum / immunology
  • Asthma / etiology
  • Asthma / physiopathology
  • Asthma / prevention & control*
  • Bronchoconstriction / drug effects
  • Bronchoconstriction / immunology
  • Bronchoconstriction / physiology
  • Cell Degranulation / drug effects
  • Disease Models, Animal
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Macaca fascicularis
  • Male
  • Mast Cells / drug effects
  • Mast Cells / immunology
  • Ovalbumin / immunology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / physiology
  • Rats
  • Rats, Inbred BN
  • Rats, Sprague-Dawley
  • Sheep
  • Signal Transduction / drug effects
  • Syk Kinase

Substances

  • Allergens
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Ovalbumin
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, rat