酪氨酸激酶抑制剂对哮喘气道重构的影响

目的探讨酪氨酸激酶抑制剂(TKIs)对支气管哮喘大鼠气道重构的影响。方法采用MTT法评价三种TKIs(Genistein、金转停及Tyrphostin AG1478)对原代培养的大鼠气管上皮细胞增殖的抑制作用；选用金转停作为哮喘大鼠模型的干预因素，采用免疫荧光法对气道上皮磷酸化酪氨酸(P—tyr)进行染色，了解气道上皮表皮生长因子受体(EGFR)的活化情况，天狼猩红染色了解气道上皮下Ⅰ、Ⅱ型胶原沉积并分析其相关性。结果三种抑制剂均对气管上皮细胞的生长具有时间及剂量依赖性抑制作用，且三者之间无明显差异；哮喘各组气道上皮下Ⅰ、Ⅱ型胶原沉积较对照组明显增高，金转停可一定程度减少胶原沉积；哮喘各组气道上皮磷酸化酪氨酸(EGFR的激活)较对照各组明显增高，而金转停干预组磷酸化酪氨酸染色明显降低。相关分析显示气道上皮下Ⅰ、Ⅱ型胶原的沉积与EGFR的激活程度明显正相关。结论酪氨酸激酶抑制剂对哮喘气道重构具有一定的防治意义。

Effect of Tyrosine Kinase Inhibitors on Airway Remodeling in Bronchial Asthma

OBJECTIVE: To investigate the effect of tyrosine kinase inhibitors (TKIs) on asthmatic rat airway remodeling. METHODS: The inhibitive effects of three TKIs (Genistein, jin-zhuan-ting and Tyrphostin AG1478) on proliferation of primary cultures of rat tracheal epithelial cells were assessed by MTT assay. Then, jin-zhuan-ting was adopted in the asthmatic rat model; immunohistofluorescene method was used to stain phosphorylated tyrosine (P-tyr) for disclosing the activation of EGFR; Sirius Red staining of submucosal collagen I and III was performed, and an analysis was made on the correlation between EGFR activation and collagen I and III deposition. RESULTS: All the three TKIs inhibited the growth of tracheal epithelial cells in a time and dose depending manner, and the inhibition rates among them showed no statistical differences; airway subepithelial collagen I and III deposition degrees were markedly elevated in asthmatic groups and jin-zhuan-ting reduced the deposition in a certain degree; EGFR activation (P-tyr) in airways epithelium of asthmatic groups was greatly increased in comparison with that of control groups, and it was evidently decreased in jin-zhuan-ting groups. Correlation analysis demonstrated that the amount of airway subepithelial collagen I and III was positively correlated to EGFR activation. CONCLUSION: TKIs may have preventive implications for asthmatic airway remodeling.