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

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

Published In Am J Respir Cell Mol Biol, (2008 Apr)

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.

PubMed ID: 18006877

MeSH Terms: Acrolein/pharmacology*; Animals; Enzyme Activation/drug effects; Gene Expression Regulation, Enzymologic/drug effects; Humans; Lung/drug effects; Lung/enzymology; Lung/pathology; MAP Kinase Signaling System/drug effects; Male; 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; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptor, Epidermal Growth Factor/metabolism; Sputum/drug effects; Sputum/enzymology; Tissue Inhibitor of Metalloproteinase-3/genetics; Tissue Inhibitor of Metalloproteinase-3/metabolism