Regulation of airway inflammation and remodeling by chemokines in bronchial asthma

Eotaxin对嗜酸性粒细胞具有趋化活性，这是哮喘发病的主要机制。表皮生长因子（EGF）是气道重塑的关键分子，在癌细胞中通过几种G蛋白偶联受体（gpcr）被反激活。我们之前发现支气管上皮细胞表达CCR3，其刺激激活MAP激酶。2003年，我们发现MAP激酶的激活是通过EGF受体（EGFR）介导的。EGFR的激活对IL-8的产生至关重要。2004年，我们在嗜酸性粒细胞中应用了受体酪氨酸激酶（RTK）转激活模型。近年来研究表明，嗜酸性粒细胞是哮喘的效应细胞，在气道重塑中起重要作用。来自一些供体的嗜酸性粒细胞在mRNA和蛋白水平上表达血小板衍生生长因子受体（PDGFR）。用PDGFR抑制剂AG1295预处理嗜酸性粒细胞后，eotaxin诱导的MAP激酶激活和趋化性明显减弱。2005年，我们在哮喘小鼠模型中检测了EGFR抑制剂AG1478对气道炎症和重塑的体内影响。AG 1478预处理可减少卵清蛋白诱导的支气管肺泡灌洗液嗜酸性粒细胞内流。组织学结果显示，AG1478显著抑制嗜酸性粒细胞的浸润、气道壁厚度和上皮细胞粘液的产生。这些结果表明EGFR在气道炎症和重塑中起关键作用。在3年的时间里，我们研究了趋化因子对变应性炎症和重塑的调节。特别是RTK转激活是过敏症调控中的一个新概念，有望应用于新的治疗策略。

Eotaxin possesses a chemotactic activity for eosinophils, which is a central mechanism in the pathogenesis of asthma. Epidermal growth factor (EGF), a key molecule in airway remodeling, is transactivated via several G protein-coupled receptors (GPCRs) in cancer cells. We have previously found that bronchial epithelial cells express CCR3 whose stimulation activates MAP kinases. In 2003, we found that the MAP kinase activation is mediated via EGF receptor (EGFR). The EGFR activation was essential for IL-8 production.In 2004, we applied the model of receptor tyrosine kinase (RTK) transactivation in eosinophils. It has recently been shown that eosinophils, effecter cells in asthma, play an important role in airway remodeling. Eosinophils from some donors express platelet-derived growth factor receptor (PDGFR) in mRNA and protein levels. After pretreatment of eosinophils with the PDGFR inhibitor AG1295, the eotaxin-induced MAP kinase activation and chemotaxis were significantly abrogated.In 2005, we examined the in vivo effect of an EGFR inhibitor AG1478 on airway inflammation and remodeling in a murine model of asthma. The ovalbumin-induced eosinophil influx in bronchoalveolar lavage fluid was reduced by pretreatment of AG 1478. In the histological findings, AG1478 significantly inhibited eosinophil infiltration, airway wall thickness, and mucus production from epithelial cells. These results suggest that EGFR has a critical role in airway inflammation and remodeling.In the 3 years' term, we investigated the regulation of allergic inflammation and remodeling modified by chemokines. Especially the RTK transactivation is a new concept in the regulation of allergy, leading to its application in new therapeutic strategy.