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  • Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production.

Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production.

American journal of respiratory cell and molecular biology (2007-11-17)
Hitesh S Deshmukh, Colleen Shaver, Lisa M Case, Maggie Dietsch, Scott C Wesselkamper, William D Hardie, Thomas R Korfhagen, Massimo Corradi, Jay A Nadel, Michael T Borchers, George D Leikauf
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
ECO Brij® L23
Sigma-Aldrich
Mucin from bovine submaxillary glands, Type I-S
Sigma-Aldrich
Anti-EGFR Antibody, neutralizing, clone LA1, clone LA1, Upstate®, from mouse
Sigma-Aldrich
Brij® L23, main component: tricosaethylene glycol dodecyl ether