Regulation of airway inflammation and remodeling by chemokines in bronchial asthma

嗜酸性粒细胞趋化因子对嗜酸性粒细胞具有趋化活性，这是哮喘发病机制中的中心机制。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）被反式激活。我们先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。2004年，我们在嗜酸性粒细胞中应用受体酪氨酸激酶（RTK）反式激活模型。近年来研究表明，嗜酸性粒细胞作为哮喘的效应细胞，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）。在用PDGFR抑制剂AG1295预处理嗜酸性粒细胞后，嗜酸性粒细胞活化趋化因子诱导的MAP激酶活化和趋化作用显著地被废除。在2005年，我们研究了EGFR抑制剂AG1478在哮喘小鼠模型中对气道炎症和重塑的体内作用。AG 1478预处理可减少卵白蛋白诱导的支气管肺泡灌洗液中嗜酸性粒细胞的流入。在组织学结果中，AG1478显著抑制嗜酸性粒细胞浸润、气道壁厚度和上皮细胞粘液产生。这些结果表明EGFR在气道炎症和重塑中起着重要作用。我们在3年的时间里研究了趋化因子对过敏性炎症和重塑的调节作用。特别是RTK反式激活是一个新的概念，在变态反应的调节，导致其在新的治疗策略的应用。

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.