Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke

Abstract

Mucus hypersecretion from hyperplastic airway goblet cells is a hallmark of chronic obstructive pulmonary disease (COPD). Although cigarette smoking is thought to be involved in mucus hypersecretion in COPD, the mechanism by which cigarette smoke induces mucus overproduction is unknown. Here we show that activation of epidermal growth factor receptors (EGFR) is responsible for mucin production after inhalation of cigarette smoke in airways in vitro and in vivo. In the airway epithelial cell line NCI-H292, exposure to cigarette smoke upregulated the EGFR mRNA expression and induced activation of EGFR-specific tyrosine phosphorylation, resulting in upregulation of MUC5AC mRNA and protein production, effects that were inhibited completely by selective EGFR tyrosine kinase inhibitors (BIBX1522, AG-1478) and that were decreased by antioxidants. In vivo, cigarette smoke inhalation increased MUC5AC mRNA and goblet cell production in rat airways, effects that were prevented by pretreatment with BIBX1522. These effects may explain the goblet cell hyperplasia that occurs in COPD and may provide a novel strategy for therapy in airway hypersecretory diseases.

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

“…Previous reports have implicated the receptor for epidermal growth factor (EGFR) 1 in the induction of mucin gene MUC5AC by smoke (9). Consistent with a role for EGFR in mucin induction, an EGF response element has been identified 200 bp upstream of the MUC5AC gene (14).…”

“…In addition, however, smoke itself can induce mucin synthesis in lung cells (8,9). The question of how this occurs is complex in that smoke, a composite of irritant molecules including acetaldehyde, hydroquinone, formaldehyde, benzo-[a]pyrene, cresol, nicotine, catechol, acrolein, coumarin, anthracene, nitrogen oxides, and heavy metals (10, 11) may act on lung epithelial cells in diverse ways.…”

Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-κB activation in normal human bronchial epithelial cells

“…Kurie et al (1996) have shown that there is increased EGFR expression in the metaplastic bronchial epithelium of smokers. Furthermore, a recent report suggests that CSC can directly stimulate the activity of the MMPs, leading to EGFR activation , in addition to causing ligand independent transactivation of the EGFR (Takeyama et al, 2001). This provides a compelling rationale for targeting MAPKs by a variety of chemopreventive measures.…”

Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect

“…Interestingly, at the two highest doses of SB-332235, the doses where the GCD appears to be elevated, there was also a significant inhibition of neutrophil infiltration. Neutrophils are thought to contribute to mucus secretion through the release of neutrophil-specific products, like elastase, which can then act directly on the epithelium (27,28). An attenuation of neutrophil numbers or activation status may therefore result in a reduction of both goblet cell exocytosis and goblet cell formation.…”