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Acrolein-Activated Matrix Metalloproteinase 9 Contributes to Persistent Mucin Production

¹ Center for Environmental Genetics, University of Cincinnati, Cincinnati; ² Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; ³ Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Parma, Italy; ⁴ CVRI, University of California San Francisco, San Francisco, California; and ⁵ Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to George Leikauf, Ph.D., University of Pittsburgh, 100 Technology Dr., Room 556, Pittsburgh, PA 15219. E-mail: gleikauf{at}pitt.edu.

Chronic obstructive pulmonary disease (COPD), a global public health problem, is characterized by progressive difficulty in breathing, with increased mucin production, especially in the small airways. Acrolein, a constituent of cigarette smoke and an endogenous mediator of oxidative stress, increases airway mucin 5, subtypes A and C (MUC5AC) production; however, the mechanism remains unclear. In this study, increased mMUC5AC transcripts and protein were associated with increased lung matrix metalloproteinase 9 (mMMP9) transcripts, protein, and activity in acrolein-exposed mice. Increased mMUC5AC transcripts and mucin protein were diminished in gene-targeted Mmp9 mice [Mmp9^(-/-)] or in mice treated with an epidermal growth factor receptor (EGFR) inhibitor, erlotinib. Acrolein also decreased mTissue inhibitor of metalloproteinase protein 3 (an MMP9 inhibitor) transcript levels. In a cell-free system, acrolein increased pro-hMMP9 cleavage and activity in concentrations (100–300 nM) found in sputum from subjects with COPD. Acrolein increased hMMP9 transcripts in human airway cells, which was inhibited by an MMP inhibitor, EGFR-neutralizing antibody, or a mitogen-activated protein kinase (MAPK) 3/2 inhibitor. Together these findings indicate that acrolein can initiate cleavage of pro-hMMP9 and EGFR/MAPK signaling that leads to additional MMP9 formation. Augmentation of hMMP9 activity, in turn, could contribute to persistent excessive mucin production.

Key Words: mucus • COPD • matrix metalloproteinase • cigarette smoke • oxidative stress

CLINICAL RELEVANCE Acrolein is a cigarette smoke component and endogenous oxidative stress product. At concentrations in chronic obstructive pulmonary disease sputum, acrolein activates matrix metalloproteinase 9 (MMP9) directly and activates epidermal growth factor receptor signaling, leading to MMP9 and MUC5AC accumulation, features of persistent mucus production.