The role of the epidermal growth factor receptor and its ligands in the regulation of the bronchial epithelial phenotype in smoking related lung disease

Abstract

Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD).  A common symptom in this condition is that of chronic mucus hypersecretion (CMH), a regular cough productive of sputum. A number of pathological changes are seen in the airways of subjects with COPD and CMH. These changes are provoked by cigarette smoke and recent evidence suggests that the epidermal growth factor receptor (EGFR), which is found in bronchial epithelial cells (BECs), plays a key role in mediating these changes.  When activated by smoke, the EGFR promotes release of pro-inflammatory cytokines from BECs and up-regulates mucin gene expression.  This is an important mechanism in the process of differentiation of epithelial cells to a mucus secreting goblet cell phenotype.  Activation of the EGFR requires cleavage of its ligands by a group of membrane-bound metalloproteinases.

In this work it is shown that any of the ligands for the EGFR found in BECs can produce an increase in expression of the pro-inflammatory cytokine interleukin 8 (IL-8) and the secreted mucin MUC5AC.  In addition an auto-induction of EGFR ligand expression is seen which may be important in modulating the effects of chronic exposure to noxious stimuli like smoke.  The effects of cigarette smoke on release of EGFR ligands with subsequent EGFR activation is confirmed with smoke promoting IL-8 release and increasing expression of both IL-8 and MUC5AC.  Doxycycline inhibits the release of EGFR ligands in BECs exposed to smoke.  This inhibition reduces the release of IL-8 from the cells and attenuates the mucin gene response.  Agents which reduce EGFR ligand shedding from BECs may provide a novel therapeutic target for treatment of CMH in smoking related lung disease.

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