title: Syk Regulates Neutrophilic Airway Hyper-Responsiveness in a Chronic Mouse Model of Allergic Airways Inflammation.
abstract: Asthma is a chronic inflammatory disease characterized by airways hyper-responsiveness (AHR), reversible airway obstruction, and airway inflammation and remodeling. We previously showed that Syk modulates methacholine-induced airways contractility in naïve mice and in mice with allergic airways inflammation. We hypothesize that Syk plays a role in the pathogenesis of AHR; this was evaluated in a chronic 8-week mouse model of house dust mite (HDM)-induced allergic airways inflammation.
  
  
  
  We used the Sykflox/flox//rosa26CreERT2 conditional Syk knock-out mice to assess the role of Syk prior to HDM exposure, and treated HDM-sensitized mice with the Syk inhibitor, GSK143, to evaluate its role in established allergic airways inflammation. Respiratory mechanics and methacholine (MCh)-responsiveness were assessed using the flexiVent® system. Lungs underwent bronchoalveolar lavage to isolate inflammatory cells or were frozen for determination of gene expression in tissues.
  
  
  
  MCh-induced AHR was observed following HDM sensitization in the Syk-intact (Sykflox/flox) and vehicle-treated BALB/c mice. MCh responsiveness was reduced to control levels in HDM-sensitized Sykdel/del mice and in BALB/c and Sykflox/flox mice treated with GSK143. Both Sykdel/del and GSK143-treated mice mounted appropriate immune responses to HDM, with HDM-specific IgE levels that were comparable to Sykflox/flox and vehicle-treated BALB/c mice. HDM-induced increases in bronchoalveolar lavage cell counts were attenuated in both Sykdel/del and GSK143-treated mice, due primarily to decreased neutrophil recruitment. Gene expression analysis of lung tissues revealed that HDM-induced expression of IL-17 and CXCL-1 was significantly attenuated in both Sykdel/del and GSK143-treated mice.
  
  
  
  Syk inhibitors may play a role in the management of neutrophilic asthma.
authors.affiliation: Division of Respirology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sepehr
authors.initials: S
authors.lastname: Salehi
authors.affiliation: Division of Respirology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Respirology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Division of Medical Sciences, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Juvet
authors.affiliation: Division of Medical Sciences, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.|Southern Ontario Center for Atmospheric Aerosol Research, Faculty of Applied Sciences, University of Toronto, Toronto, Ontario, Canada.|Division of Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.|Department of Health Sciences, Faculty of Health and Behavioural Sciences, Lakehead University, Thunder Bay, Ontario, Canada.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Scott
authors.affiliation: Division of Respirology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Southern Ontario Center for Atmospheric Aerosol Research, Faculty of Applied Sciences, University of Toronto, Toronto, Ontario, Canada.|Division of Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.|Multi-Organ Transplant Programme, University Health Network, Toronto, Ontario, Canada.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Chow
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000201:enzymology*; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D039981:Pyroglyphidae / Q000276:immunology; D000072377:Syk Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072377:Syk Kinase; C000606897:Syk protein, mouse