title: Inhibition of spleen tyrosine kinase attenuates allergen-mediated airway constriction.
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.
authors.affiliation: 1 In Vivo Pharmacology.
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Jia
authors.forename: Michael
authors.initials: M
authors.lastname: Caniga
authors.forename: Gissela
authors.initials: G
authors.lastname: Lieber
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Gil
authors.forename: Xiomara
authors.initials: X
authors.lastname: Fernandez
authors.forename: Erich
authors.initials: E
authors.lastname: Sirkowski
authors.forename: Richard
authors.initials: R
authors.lastname: Miller
authors.forename: Jessica P
authors.initials: JP
authors.lastname: Alexander
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Lee
authors.forename: John D
authors.initials: JD
authors.lastname: Shin
authors.forename: J Michael
authors.initials: JM
authors.lastname: Ellis
authors.forename: Hongmin
authors.initials: H
authors.lastname: Chen
authors.forename: Alan
authors.initials: A
authors.lastname: Wilhelm
authors.forename: Hongshi
authors.initials: H
authors.lastname: Yu
authors.forename: Stella
authors.initials: S
authors.lastname: Vincent
authors.forename: Richard W
authors.initials: RW
authors.lastname: Chapman
authors.forename: Nancy
authors.initials: N
authors.lastname: Kelly
authors.forename: Emily
authors.initials: E
authors.lastname: Hickey
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.forename: Alan
authors.initials: A
authors.lastname: Northrup
authors.forename: Thomas
authors.initials: T
authors.lastname: Miller
authors.forename: Hani
authors.initials: H
authors.lastname: Houshyar
authors.forename: Michael A
authors.initials: MA
authors.lastname: Crackower
mesh_terms: D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D017165:Ascaris suum / Q000276:immunology; D001249:Asthma / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D016084:Bronchoconstriction / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D015550:Cell Degranulation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008252:Macaca fascicularis; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase
chemical_list: D000485:Allergens; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat