在小鼠哮喘模型中抑制Pyk2能阻断气道炎症和气道高反应性
2009/08/11
Pyk2是炎症细胞粘附后迁移所需要的一种细胞内非受体型蛋白酪氨酸激酶。本实验的目的是研究Pyk2对免疫致敏小鼠的气道炎症和气道高反应性的作用。
通过腹腔给予TAT-Pyk2-CT（C端负显性的Pyk2 与TAT 蛋白转导结构域连接）阻断Pyk2。在免疫致敏的小鼠中，用卵清蛋白可以刺激诱导气道嗜酸性粒细胞和淋巴细胞浸润，增加粘液上皮细胞、诱导气道对乙酰甲胆碱的高反应性。
腹腔给予10 mg/kg TAT-Pyk2-CT能阻断上述所有效应，而且能降低BAL液内的Th2细胞因子IL-4, IL-5 和IL-13分泌量。鼻内给予IL-5能导致嗜酸性粒细胞向气道管腔内迁移，但全身给予TAT-Pyk2-CT却能抑制这一效应。对照组采用TAT-GFP，未能阻断上述效应。
我们认为，在体外试验中，Pyk2是炎症细胞迁移的必须因素，在用卵清蛋白致敏的小鼠哮喘模型进行的体内抗原刺激试验中，Pyk2能调节抗原刺激诱导的气道炎症、Th2细胞因子分泌量和气道高反应性。
（苏楠 审校）
Duan Y, et al. Am J Respir Cell Mol Biol. 2009 Jun 11. [Epub ahead of print]
Inhibition of Pyk2 Blocks Airway Inflammation and Hyperresponsiveness in a Mouse Model of Asthma.
Duan Y, Learoyd J, Meliton AY, Clay BS, Leff AR, Zhu X.
Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States.
The objective of this investigation was to determine the role of Pyk2, an intracellular non-receptor protein tyrosine kinase for post-adhesive inflammatory cell migration, on airway inflammation and hyperresponsiveness in immune sensitized mice. Blockade of Pyk2 was effected by intraperitonial 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 i.p. blocked all of these effects and further decreased secretion of Th2 cytokine IL-4, IL-5 and IL-13 into the BAL 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.
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