Epidermal growth factor system regulates mucin production in airways
Epidermal growth factor system regulates mucin production in airways
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DOI：
10.1073/pnas.96.6.3081
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发表时间：
1999-03-16
影响因子：
11.1
通讯作者：
Nadel, JA
中科院分区：
文献类型：
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作者：
Takeyama, K;Dabbagh, K;Nadel, JA
杯状细胞增生是气道高分泌性疾病的重要病理特征。然而，其潜在机制尚不清楚，也没有有效的治疗方法。在这里，我们表明，刺激表皮生长因子受体（EGF-R）的配体，EGF和转化生长因子α（TGF α），导致MUC 5AC在气道上皮细胞在体外和体内的表达。我们发现MUC 5AC诱导的上皮细胞系NCI-H292组成型表达EGF-R; EGF-R基因表达被肿瘤坏死因子α（TNF α）进一步刺激。EGF-R配体在基因和蛋白水平上增加MUC 5AC的表达，并且这种作用被TNF α增强。选择性EGF-R酪氨酸激酶抑制剂阻断EGF-R配体诱导的MUC 5AC表达。无病原体的大鼠在气道上皮细胞中表达很少的EGF-R蛋白;气管内滴注TNF α诱导气道上皮细胞中的EGF-R，随后滴注EGF-R配体增加杯状细胞的数量、阿辛蓝-高碘酸-希夫染色（反映粘液糖缀合物）和MUC 5AC基因表达，而单独的TNF α、EGF或TGF α没有影响。在致敏大鼠中，三次卵清蛋白气管内滴注导致气道上皮中EGF-R表达和杯状细胞产生。用EGF-R酪氨酸激酶抑制剂BIBX 1522预处理，可阻止TNF α-EGF-R配体刺激的大鼠和哮喘模型中杯状细胞的产生。这些发现表明EGF-R级联抑制剂在气道高分泌性疾病中的潜在作用。
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 (TGF alpha), 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 (TNF alpha). EGF-R ligands increased the expression of;MUC5AC at both gene and protein levels, and this effect was potentiated by TNF alpha. 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 TNF alpha 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 TNF alpha, EGF, or TGF alpha 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 TNF alpha-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.