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Published ahead of print on November 5, 2004, doi:10.1164/rccm.200408-1003OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 4, February 2005, 305-314

A more recent version of this article appeared on February 15, 2005
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Submitted on August 4, 2004
Accepted on November 3, 2004

Metalloproteinases Mediate Mucin5AC Expression by Epidermal Growth Factor Receptor Activation

Hitesh S Deshmukh1, Lisa M Case1, Scott C Wesselkamper1, Michael T Borchers2, Linda Martin1, Howard G Shertzer3, Jay A Nadel4, and George D Leikauf2*

1 Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA, 2 Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA; Department of Pulmonary and Critical Care Medicine, University of Cincinnati, Cincinnati, OH, USA, 3 Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA, 4 Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, CA, USA

* To whom correspondence should be addressed. E-mail: leikaugd{at}uc.edu.

Chronic obstructive pulmonary disease (COPD) is marked by alveolar enlargement and excess production of airway mucus. Acrolein, a component of cigarette smoke increases 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 ≥ 10 µM, 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 [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 (siRNA) 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 metalloprotienase-3 (TIMP3), an endogenous inhibitor of ADAM17, transcripts. Taken 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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