title: Inhibition of Pyk2 blocks airway inflammation and hyperresponsiveness in a mouse model of asthma.
abstract: The objective of this investigation was to determine the role of Pyk2, an intracellular nonreceptor protein tyrosine kinase for postadhesive inflammatory cell migration, on airway inflammation and hyperresponsiveness in immune-sensitized mice. Blockade of Pyk2 was effected by intraperitoneal administration of dominant-negative C-terminal Pyk2 fused to a TAT protein transduction domain (TAT-Pyk2-CT). Ovalbumin challenge elicited infiltration of both eosinophils and lymphocytes into airways, increased mucus-containing epithelial cells, and caused increased airway hyperresponsiveness to methacholine in immune-sensitized mice. Pretreatment with 10 mg/kg TAT-Pyk2-CT intraperitoneally blocked all of these effects and further decreased secretion of Th2 cytokine IL-4, IL-5, and IL-13 into the bronchoalveolar lavage fluid. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by systemic pretreatment with TAT-Pyk2-CT. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. We conclude that Pyk2, which is essential for inflammatory cell migration in vitro, regulates airway inflammation, Th2 cytokine secretion, and airway hyperresponsiveness in the ovalbumin-sensitized mice during antigen challenge in vivo.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Duan
authors.forename: Jonathan
authors.initials: J
authors.lastname: Learoyd
authors.forename: Angelo Y
authors.initials: AY
authors.lastname: Meliton
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Clay
authors.forename: Alan R
authors.initials: AR
authors.lastname: Leff
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000941:Antigens / Q000009:adverse effects / Q000494:pharmacology; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D018418:Th2 Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D000941:Antigens; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse