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Metalloproteinases Mediate Mucin 5AC Expression by Epidermal Growth Factor Receptor Activation

Departments of Environmental Health and Pulmonary and Critical Care Medicine, University of Cincinnati, Cincinnati, Ohio; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina; Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California–San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to George D. Leikauf, Ph.D., University of Cincinnati, P.O. Box 670056, Cincinnati, OH 45267-0056. E-mail: leikaugd{at}uc.edu

Chronic obstructive pulmonary disease is marked by alveolar enlargement and excess production of airway mucus. Acrolein, a component of cigarette smoke, increases mucin 5AC (MUC5AC), a prevalent airway mucin in NCI-H292 cells by transcriptional activation, but the signal transduction pathways involved in acrolein-induced MUC5AC expression are unknown. Acrolein depleted cellular glutathione at doses of 10 µM or greater, higher than those sufficient (0.03 µM) to increase MUC5AC mRNA, suggesting that MUC5AC expression was independent of oxidative stress. In contrast, acrolein increased MUC5AC mRNA levels by phosphorylating epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase 3/2, or MAPK 3/2(ERK1/2). Pretreating the cells with an EGFR-neutralizing antibody, or a metalloproteinase inhibitor, decreased the acrolein-induced MUC5AC mRNA increase. Small, interfering RNA directed against ADAM17 or MMP9 inhibited the acrolein-induced MUC5AC mRNA increase. Acrolein increased the release and subsequent activation of pro-MMP9. Acrolein increased MMP9 and decreased tissue inhibitor of metalloproteinase 3 (TIMP3), an endogenous inhibitor of ADAM17, transcripts. Together, these data suggest that acrolein induces MUC5AC expression via an initial ligand-dependent activation of EGFR mediated by ADAM17 and MMP9. In addition, a prolonged effect of acrolein may be mediated by altering MMP9 and TIMP3 transcription.

Key Words: bronchitis • emphysema • human bronchial epithelial cells • mucin

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