Regulation of cigarette smoke-mediated mucin expression by hypoxia-inducible factor-1[alpha] via epidermal growth factor receptor-mediated signaling pathways

• Published in: Journal of applied toxicology 2012-04, Vol.32 (4), p.282
• Main Authors: Yu, Hongmei, Li, Qi, Kolosov, Victor P, Perelman, Juliy M, Zhou, Xiangdong
• Format: Article
• Language: English
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.1679

Cigarette smoking is strongly implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Mucus hypersecretion is the key manifestation in patients with COPD and mucin 5AC (MUC5AC) is a major component of airway mucus. Hypoxia inducible factor-1 (HIF-1) is a transcriptional factor which can be stimulated to bind to the MUC5AC promoter and induce MUC5AC promoter activation. Previous studies have reported that activation of HIF-1[alpha] pathways by cigarette smoke contributes to the development of COPD. We hypothesize that cigarette smoke up-regulates HIF-1[alpha] production and HIF-1 activity through epidermal growth factor receptor (EGFR)-activated signal cascades pathways, leading to mucin production in human airway epithelial cells (16HBE). We show that cigarette smoke increases HIF-1[alpha] production, HIF-1 activity and MUC5AC expression. These effects are prevented by small interfering RNA (siRNA) for HIF-1[alpha], indicating that cigarette smoke-induced mucin production is HIF-1[alpha]-dependent. Cigarette smoke activates extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K) signal pathways, both of which are inhibited by gefitinib (an inhibitor of EGFR), suggesting that cigarette smoke-activated signal pathways are mediated by EGFR in 16HBE cells. Furthermore, pretreatment with gefitinib and the pharmacological inhibitors of PI3K (LY294002) and ERK1/2 (PD98059) prevented cigarette smoke-mediated Akt and ERK1/2 phosphorylation responses, HIF-1[alpha] production, HIF-1 activity and MUC5AC expression. These observations demonstrate an important role for EGFR-mediated signaling pathways in regulating cigarette smoke-induced HIF-1 activation and MUC5AC expression. Our results suggest that cigarette smoke activates EGFR-mediated signaling pathways, leading to HIF-1[alpha] production and HIF-1 activation, resulting in mucin expression in human airway epithelial cells. Copyright © 2011 John Wiley & Sons, Ltd. Cigarette smoke increases HIF-1[alpha] production, HIF-1 activity and MUC5AC expression in 16HBE cells, effects that are prevented HIF-1[alpha] siRNA. Cigarette smoke activates ERK1/2 and PI3K signal pathways by EGFR. The pharmacological inhibitors of EGFR, PI3K (LY294002) and ERK1/2 (PD98059) prevented cigarette smoke-mediated Akt and ERK1/2 phosphorylation responses, HIF-1[alpha] production, HIF-1 activity and MUC5AC expression. These results suggest that cigarette smoke activates EGFR-mediate