Epidermal growth factor system regulates mucin production in airways

Goblet-cell hyperplasia is a critical pathological feature in hypersecretor y diseases of airways. However, the underlying mechanisms are unknown, and no effective therapy exists. Here we show that stimulation of epidermal gro wth factor receptors (EGF-R) by its ligands, EGF and transforming growth fa ctor alpha (TGF alpha), causes MUC5AC expression in airway epithelial cells both in in vitro and in vivo. We found that a MUC5AC-inducing epithelial c ell line, NCI-H292, expresses EGF-R constitutively; EGF-R gene expression w as stimulated further by tumor necrosis factor alpha (TNF alpha). EGF-R lig ands increased the expression of;MUC5AC at both gene and protein levels, an d this effect was potentiated by TNF alpha. Selective EGF-R tyrosine kinase inhibitors blocked MUC5AC expression induced by EGF-R ligands. Pathogen-fr ee rats expressed little EGF-R protein in airway epithelial cells; intratra cheal instillation of TNF alpha induced EGF-R in airway epithelial cells, a nd subsequent instillation of EGF-R ligands increased the number of goblet cells, Alcian blue-periodic acid-Schiff staining (reflecting mucous glycoco njugates), and MUC5AC gene expression, whereas TNF alpha, EGF, or TGF alpha alone was without effect. In sensitized rats, three intratracheal instilla tions of ovalbumin resulted in EGF-R expression and goblet-cell production in airway epithelium. Pretreatment with EGF-R tyrosine kinase inhibitor, BI BX1522, prevented goblet-cell production both in rats stimulated by TNF alp ha-EGF-R Ligands and in an asthma model. These findings suggest potential r oles for inhibitors of the EGF-R cascade in hypersecretory diseases of airw ays.