Chronic bronchitis is associated with hyperplasia of both epithelial goblet cells and submucosal glands in the airways. Mucins, which are complex glycoproteins that provide the viscoelastic properties of mucus, are an essential protective mechanism in the upper airways. The regulation of mucins is altered in the lungs of COPD patients. The airways of smokers contain more goblet cells than do those of nonsmo-kers and goblet-cell activation results in mucus hypersecretion leading to airway plugging (125). Cigarette smoke can activate epidermal growth factor (EGF) receptors by tyrosine phosphorylation, resulting in the induction of mucin (MUCI-N5AC gene expression) synthesis in epithelial cells and in vivo in lungs (126). Cigarette smoke-mediated via MUC5AC gene expression was inhibited by selective EGF receptor tyrosine kinase inhibitors and antioxidants (127). Oxidant-generating systems, such as xanthine/xanthine oxidase, have been shown to cause the release of mucus from airway epithelial cells (128). It has also been shown that elastase released from neutrophils impairs mucociliary clearance and stimulates goblet-cell metaplasia and mucin production. Neutrophil elastase increases the expression of MUC5AC by enhancing mRNA stability (129). Understanding of the EGF receptor signaling pathway in cigarette smoke-mediated upregulation of mucin gene expression could lead to targeted inhibition of mucus hyperproduction in epithelial cells.
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