Inhibition of Pyk2 Blocks Airway Inflammation and Hyperresponsiveness in a Mouse Model of Asthma

被引:24
作者
Duan, Yingli [1 ]
Learoyd, Jonathan [1 ]
Meliton, Angelo Y. [1 ]
Clay, Bryan S. [1 ]
Leff, Alan R. [1 ,2 ,3 ,4 ,5 ,6 ]
Zhu, Xiangdong [1 ]
机构
[1] Univ Chicago, Dept Med, Pulm & Crit Care Med Sect, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA
[3] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA
[4] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA
[5] Univ Chicago, Dept Comm Clin Pharmacol, Chicago, IL 60637 USA
[6] Univ Chicago, Dept Cell Physiol & Mol Med, Div Biol Sci, Chicago, IL 60637 USA
关键词
eosinophils; Pyk2; inflammation; lung; RICH TYROSINE KINASE-2; PROTEIN TRANSDUCTION; MURINE MODEL; EOSINOPHILS; CELLS; INTERLEUKIN-5; MIGRATION; MICE; ACTIVATION; EOTAXIN;
D O I
10.1165/rcmb.2008-0469OC
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:491 / 497
页数:7
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