Acrolein-Activated Matrix Metalloproteinase 9 Contributes to Persistent Mucin Production

• Published in: American journal of respiratory cell and molecular biology Vol. 38; no. 4; pp. 446 - 454
• Main Authors: Deshmukh, Hitesh S, Shaver, Colleen, Case, Lisa M, Dietsch, Maggie, Wesselkamper, Scott C, Hardie, William D, Korfhagen, Thomas R, Corradi, Massimo, Nadel, Jay A, Borchers, Michael T, Leikauf, George D
• Format: Journal Article
• Language: English
• Published: United States Am Thoracic Soc 01-04-2008; American Thoracic Society
• Subjects: Acrolein - pharmacology; Animals; Enzyme Activation - drug effects; Gene Expression Regulation, Enzymologic - drug effects; Humans; Lung - drug effects; Lung - enzymology; Lung - pathology; Male; MAP Kinase Signaling System - drug effects; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mucin 5AC; Mucins - biosynthesis; Mucins - genetics; Mucins - metabolism; Pulmonary Disease, Chronic Obstructive - enzymology; Pulmonary Disease, Chronic Obstructive - pathology; Receptor, Epidermal Growth Factor - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sputum - drug effects; Sputum - enzymology; Tissue Inhibitor of Metalloproteinase-3 - genetics; Tissue Inhibitor of Metalloproteinase-3 - metabolism
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2006-0339OC

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.