title: Spleen tyrosine kinase inhibition blocks airway constriction and protects from Th2-induced airway inflammation and remodeling.
abstract: BACKGROUND
  Spleen tyrosine kinase (Syk) is an intracellular nonreceptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allergen sensitization remain elusive.
  
  
  METHODS
  Spectral confocal microscopy of human and murine lung tissue was performed to localize Syk expression. The effects of prophylactic or therapeutic Syk inhibition on allergic airway inflammation, hyperresponsiveness, and airway remodeling were analyzed in allergen-sensitized and airway-challenged mice. The effects of Syk inhibitors BAY 61-3606 or BI 1002494 on airway function were investigated in isolated lungs of wild-type, PKCα-deficient, mast cell-deficient, or eNOS-deficient mice.
  
  
  RESULTS
  Spleen tyrosine kinase expression was found in human and murine airway smooth muscle cells. Syk inhibition reduced allergic airway inflammation, airway hyperresponsiveness, and pulmonary collagen deposition. In naïve mice, Syk inhibition diminished airway responsiveness independently of mast cells, or PKCα or eNOS expression and rapidly reversed established bronchoconstriction independently of NO. Simultaneous inhibition of Syk and PKC revealed additive dilatory effects, whereas combined inhibition of Syk and rho kinase or Syk and p38 MAPK did not cause additive bronchodilation.
  
  
  CONCLUSIONS
  Spleen tyrosine kinase inhibition directly attenuates airway smooth muscle cell contraction independent of its protective immunomodulatory effects on allergic airway inflammation, hyperresponsiveness, and airway remodeling. Syk mediates bronchoconstriction in a NO-independent manner, presumably via rho kinase and p38 MAPK, and Syk inhibition might present a promising therapeutic approach in chronic asthma as well as acute asthma attacks.
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Biberach, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Tabeling
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Biberach, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Herbert
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Biberach, Germany.
authors.forename: A C
authors.initials: AC
authors.lastname: Hocke
authors.affiliation: Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lamb
authors.affiliation: Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: S L
authors.initials: SL
authors.lastname: Wollin
authors.affiliation: Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: K J
authors.initials: KJ
authors.lastname: Erb
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Biberach, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Boiarina
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Movassagh
authors.affiliation: Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Scheffel
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Biberach, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Doehn
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Biberach, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hippenstiel
authors.affiliation: Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Maurer
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: A S
authors.initials: AS
authors.lastname: Gounni
authors.affiliation: Department of Physiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|The Keenan Research Centre for Biomedical Science of St. Michael's, University of Toronto, Toronto, ON, Canada.|Departments of Physiology and Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: W M
authors.initials: WM
authors.lastname: Kuebler
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Biberach, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Suttorp
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Biberach, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Witzenrath
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects* / Q000276:immunology*; D000485:Allergens / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016084:Bronchoconstriction / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051571:Protein Kinase C-alpha; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C477642:2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; D000485:Allergens; C000619117:BI 1002494; D018836:Inflammation Mediators; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011760:Pyrrolidinones; D009536:Niacinamide; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D000072377:Syk Kinase; D051571:Protein Kinase C-alpha; D051606:G-Protein-Coupled Receptor Kinase 1; C496764:GRK1 protein, human; D048051:p38 Mitogen-Activated Protein Kinases
keywords: airway remodeling; airway responsiveness; asthma; bronchoconstriction; p38 MAPK