Epidermal Growth Factor Receptor Inhibitor Ag1478 Inhibits Mucus Hypersecretion in Airway Epithelium
Epidermal Growth Factor Receptor Inhibitor Ag1478 Inhibits Mucus Hypersecretion in Airway Epithelium
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DOI：
10.2500/ajra.2016.30.4263
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发表时间：
2016-01
影响因子：
2.6
通讯作者：
Kumiko Takezawa;T. Ogawa;S. Shimizu;Takeshi Shimizu
中科院分区：
文献类型：
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作者：
Kumiko Takezawa;T. Ogawa;S. Shimizu;Takeshi Shimizu
背景气道粘液高分泌和中性粒细胞浸润是气道炎症的重要特征。表皮生长因子受体（EGFR）反式激活诱导气道上皮细胞分泌粘液和炎性细胞因子。为了阐明EGFR在气道炎症中的作用，检测了EGFR酪氨酸激酶抑制剂AG 1478对体外培养的气道上皮细胞的粘蛋白产生和白细胞介素（IL）8分泌的影响以及对大鼠鼻粘膜中粘液高分泌和中性粒细胞浸润的体内影响。方法体外观察AG 1478处理NCI-H292细胞对脂多糖（LPS）或肿瘤坏死因子（TNF）a诱导的MUC 5AC粘蛋白和IL-8分泌的影响。鼻内滴注LPS诱导大鼠鼻黏膜上皮杯状细胞增生、化生、粘液分泌和中性粒细胞浸润，并观察腹腔注射和鼻内滴注AG 1478的抑制作用。结果AG 1478（1-1000 nM）可明显抑制LPS和TNF-α诱导的NCI-H292细胞分泌MUC 5AC和IL-8，并呈剂量依赖性。MUC 5AC和IL-8信使RNA的表达也被显著抑制。鼻内LPS滴注后1小时鼻内滴注AG 1478显著抑制LPS诱导的大鼠鼻上皮杯状细胞化生、粘液产生和中性粒细胞浸润，与LPS滴注前1小时腹腔内注射AG 1478一样。结论EGFR反式激活在气道上皮细胞分泌粘蛋白和IL-8中起重要作用。鼻内滴注EGFR酪氨酸激酶抑制剂可能是治疗上气道炎症的一种新的治疗方法。
Background Mucus hypersecretion and neutrophil infiltration are important characteristics of airway inflammation. Epidermal growth factor receptor (EGFR) transactivation induces mucus and inflammatory cytokine secretion from airway epithelial cells. To elucidate the roles of EGFR in airway inflammation, the in vitro effects on mucin production and interleukin (IL) 8 secretion from cultured airway epithelial cells and the in vivo effects on mucus hypersecretion and neutrophil infiltration in rat nasal mucosa of the EGFR tyrosine kinase inhibitor AG1478 were examined. Methods The in vitro effects of AG1478 treatment of cultured NCI-H292 cells on lipopolysaccharide (LPS) induced or tumor necrosis factor (TNF) a induced MUC5AC mucin and IL-8 secretion were evaluated. Hypertrophic and metaplastic changes of goblet cells, mucus production and neutrophil infiltration in rat nasal epithelium were induced by intranasal instillation of LPS in vivo, and the inhibitory effects of AG1478 by intraperitoneal injection or intranasal instillation were examined. Results AG1478 (1-1000 nM) significantly inhibited both LPS-induced and TNF-α-induced secretion of MUC5AC and IL-8 from cultured NCI-H292 cells in a dose-dependent manner. The expression of MUC5AC and IL-8 messenger RNAs was also significantly inhibited. Intranasal instillation of AG1478 one hour after intranasal LPS instillation significantly inhibited LPS-induced goblet cell metaplasia, mucus production, and neutrophil infiltration in rat nasal epithelium, as did intraperitoneal injection of AG1478 one hour before LPS instillation. Conclusions These results indicated that EGFR transactivation plays an important role in mucin and IL-8 secretion from airway epithelial cells. Intranasal instillation of an EGFR tyrosine kinase inhibitor may be a new therapeutic approach for the treatment of upper airway inflammation.