Regulation of airway inflammation and remodeling by chemokines in bronchial asthma

嗜酸细胞趋化因子对嗜酸性粒细胞具有趋化活性，这是哮喘发病的中心机制。表皮生长因子(EGF)是呼吸道重塑的关键分子，通过癌细胞上的几个G蛋白偶联受体(GPCRs)反式激活。我们先前已经发现，支气管上皮细胞表达CCR3，CCR3的刺激激活了MAP激酶。2003年，我们发现MAP的激活是通过表皮生长因子受体(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)反式激活的模型。近年来的研究表明，嗜酸性粒细胞作为哮喘的效应细胞，在气道重塑中发挥着重要作用。一些捐献者的嗜酸性粒细胞在mRNA和蛋白水平表达血小板衍生生长因子受体(PDGFR)。在用PDGFR抑制剂AG1295预处理嗜酸粒细胞后，嗜酸性粒细胞诱导的MAP激酶活化和趋化作用被显著取消。2005年，我们在体内观察了EGFR抑制剂AG1478对哮喘小鼠模型气道炎症和重塑的影响。AG 1478可减少卵蛋白诱导的嗜酸性粒细胞进入支气管肺泡灌洗液。在组织学结果中，AG1478显著抑制嗜酸性粒细胞的渗透、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着关键作用。在这3年的研究中，我们研究了趋化因子对变态反应性炎症和重塑的调节。尤其是RTK反式激活是变态反应调控中的一个新概念，使其在新的治疗策略中得到应用。

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.