Takeyama K, Dabbagh K, Lee H M, Agustí C, Lausier J A, Ueki I F, Grattan K M, Nadel J A
Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0130, USA.
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3081-6. doi: 10.1073/pnas.96.6.3081.
Goblet-cell hyperplasia is a critical pathological feature in hypersecretory diseases of airways. However, the underlying mechanisms are unknown, and no effective therapy exists. Here we show that stimulation of epidermal growth factor receptors (EGF-R) by its ligands, EGF and transforming growth factor alpha (TGFalpha), causes MUC5AC expression in airway epithelial cells both in in vitro and in vivo. We found that a MUC5AC-inducing epithelial cell line, NCI-H292, expresses EGF-R constitutively; EGF-R gene expression was stimulated further by tumor necrosis factor alpha (TNFalpha). EGF-R ligands increased the expression of MUC5AC at both gene and protein levels, and this effect was potentiated by TNFalpha. Selective EGF-R tyrosine kinase inhibitors blocked MUC5AC expression induced by EGF-R ligands. Pathogen-free rats expressed little EGF-R protein in airway epithelial cells; intratracheal instillation of TNFalpha induced EGF-R in airway epithelial cells, and subsequent instillation of EGF-R ligands increased the number of goblet cells, Alcian blue-periodic acid-Schiff staining (reflecting mucous glycoconjugates), and MUC5AC gene expression, whereas TNFalpha, EGF, or TGFalpha alone was without effect. In sensitized rats, three intratracheal instillations of ovalbumin resulted in EGF-R expression and goblet-cell production in airway epithelium. Pretreatment with EGF-R tyrosine kinase inhibitor, BIBX1522, prevented goblet-cell production both in rats stimulated by TNFalpha-EGF-R ligands and in an asthma model. These findings suggest potential roles for inhibitors of the EGF-R cascade in hypersecretory diseases of airways.
杯状细胞增生是气道高分泌疾病的关键病理特征。然而，其潜在机制尚不清楚，且尚无有效的治疗方法。在此我们表明，表皮生长因子受体（EGF-R）的配体表皮生长因子（EGF）和转化生长因子α（TGFα）对其的刺激，在体外和体内均可导致气道上皮细胞中MUC5AC的表达。我们发现，一种诱导MUC5AC表达的上皮细胞系NCI-H292组成性表达EGF-R；肿瘤坏死因子α（TNFα）可进一步刺激EGF-R基因表达。EGF-R配体在基因和蛋白质水平上均增加了MUC5AC的表达，且TNFα可增强这种作用。选择性EGF-R酪氨酸激酶抑制剂可阻断EGF-R配体诱导的MUC5AC表达。无特定病原体的大鼠气道上皮细胞中几乎不表达EGF-R蛋白；气管内滴注TNFα可诱导气道上皮细胞表达EGF-R，随后滴注EGF-R配体可增加杯状细胞数量、阿尔辛蓝-过碘酸-希夫染色（反映黏液糖缀合物）以及MUC5AC基因表达，而单独使用TNFα、EGF或TGFα则无此作用。在致敏大鼠中，气管内三次滴注卵清蛋白可导致气道上皮细胞中EGF-R表达和杯状细胞生成。用EGF-R酪氨酸激酶抑制剂BIBX1522预处理可预防TNFα-EGF-R配体刺激的大鼠以及哮喘模型中的杯状细胞生成。这些发现提示EGF-R级联反应抑制剂在气道高分泌疾病中可能发挥作用。
